Non-steroidal progesterone receptor modulators

ABSTRACT

The present invention provides compounds according to general Formula (I), a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a prodrug thereof. More particularly, the present invention provides high affinity non-steroidal compounds which are agonists, partial agonists or antagonists of the progesterone receptor.

The present invention relates to progesterone receptor modulatingcompounds as well as to the use of these compounds in therapy.

Intracellular receptors are a class of structurally related proteinsinvolved in the regulation of gene proteins. Steroid receptors are asubset of these receptors, including the progesterone receptor (PR),androgen receptor (AR), estrogen receptor (ER), glucocorticoid receptor(GR) and mineralocorticoid receptor (MR). Regulation of a gene by suchfactors requires the intracellular receptor and a corresponding ligandwhich has the ability to selectively bind to the receptor in a way thataffects gene transcription.

Progesterone receptor modulators (progestagens) are known to play a nimportant role in the health of women. The natural ligand for the PRreceptor is the steroid hormone progesterone, but synthetic compoundshave been made which may also serve as ligands (see e.g. Jones et alU.S. Pat. No. 5,688,810).

Progestagens are currently widely used for hormonal contraception and inHRT. Other important clinical applications of progestagens are treatmentof gynaecological disorders (e.g. endometriosis, dysmenorrhea,dysfunctional uterine bleeding, severe premenstrual syndrome), breastcancer, and luteal support during IVF. PR agonists are used in birthcontrol formulations, whereas PR antagonists may be used incontraception, hormone dependent cancers, hormone displacement therapy,endometriosis etc.

The current steroidal progestagens have been proven to be quite safe andare well tolerated. Sometimes, however, side effects (e.g. breasttenderness, headaches, depression, and weight gain) have been reportedthat are attributed to these steroidal progestagens, either alone or incombination with estrogenic compounds.

Steroidal ligands for one receptor often show cross-reactivity withother steroidal receptors. Many progestagens also bind e.g. to theglucocorticoid receptor. Non-steroidal progestagens have no molecularstructural similarity with steroids and therefore one might also expectdifferences in physicochemical properties, pharmacokinetic (PK)parameters, tissue distribution (e.g. CNS versus peripheral) and, moreimportantly, non-steroidal progestagens may show no/lesscross-reactivity to other steroid receptors. Therefore, non-steroidalprogestagens will score differently in these respects.

The present invention provides non-steroidal compounds that modulateprogesterone receptor activity. More particularly, the present inventionprovides high affinity non-steroidal compounds which are agonists,partial agonists or antagonists of the progesterone receptor. Preferablythese compounds are highly specific for the progesterone receptor.According to the present invention compounds are provided having ageneral Formula I, a prodrug thereof, or a pharmaceutically acceptablesalt of either the compound or the prodrug.

wherein

-   R1, R3, R4, R5 and R10 independently are selected from the group    consisting of H, halogen, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl,    OH, CN, O(1-4C)alkyl, S(O)_(m)(1-4C)alkyl (optionally substituted    with one or more halogen atoms), C(O)(1-4C)alkyl, OC(O)(1-4C)alkyl    and NR19R20,-   R2 is selected from the group consisting of H, halogen, NO₂,    NR11R12, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, OH,    O(1-4C)alkyl, S(1-4C)alkyl and OC(O)(1-4C)alkyl,-   R6 is selected from the group consisting of H, C(Y)R15, C(O)OR16,    C(S)NR17, (1-6C)alkyl, (1-6C)alkoxy-substituted (1-4C)alkyl and    (CH₂)_(n)C(O)OR21,-   R7 is selected from the group consisting of (1-4C)alkyl,    (2-4C)alkenyl and (2-4C)alkynyl, all optionally substituted with one    or more halogen atoms or R7 is H.-   R8 and R9 independently are selected from the group consisting of H    and (1-4C)alkyl,-   R11 and R12 independently are selected from the group consisting of    H, (1-4C)alkyl, (2-4C)alkenyl or (2-4C)alkynyl,    (1-6C)alkoxycarbonyl, (1-4C)alkylsulfonyl and (6-10C)arylsulfonyl,-   R15 is H or R15 is selected from the group consisting of    (1-6C)alkyl, (3-6C)cycloalkyl, (2-4C)alkenyl, (2-4C)alkynyl,    (6-10C)aryl, 1,4-bisaryl, amino(1-4C)alkyl, hydroxy(1-4C)alkyl, and    carboxy(1-4C)alkyl, all optionally substituted with one or more    halogen atoms,-   R16 is (1-6C)alkyl, optionally substituted with one or more halogen    atoms,-   R17 is selected from the group consisting of (1-4C)alkyl,    (2-4C)alkenyl, (2-4C)alkynyl and (3-6C)cycloalkyl, all optionally    substituted with one or more halogen atoms,-   X is selected from the group consisting of O, S, CH₂ and NR18,-   Y is selected from the group consisting of O, S, and NH,-   R18 is selected from the group consisting of H and (1-4C)alkyl,-   R19 is selected from the group consisting of H and (1-4C)alkyl,-   R20 is selected from the group consisting of H, (1-4C)alkyl,    CH₂(6-10C)aryl, C(O)(1-6C)alkyl and C(O)NH(1-4C)alkyl,-   R21 is selected from the group consisting of H and (1-6C)alkyl,-   m is 0, 1 or 2, and-   n is 1, 2 or 3,    provided that-   (i) when X is O, R1-R5 are H, R8-R10 are H, and R6 is ethyl or    C(O)CH 3 then R7 is not H;-   (ii) when X is O, R1-R5 are H, R8-R10 are H, and R6 is methyl then    R7 is not methyl; and-   (iii) when X is O, R1-R5 are H, R8-R10 are H and R6 is H then R7 is    not H or ethyl or (CO)CH₃.

The term (1-4C)alkyl as used in the definition of the invention means abranched or unbranched alkyl group having 1-4 carbon atoms, for examplemethyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl.

The term (1-6C)alkyl as used in the definition of the invention means abranched or unbranched alkyl group having 1-6 carbon atoms, for examplemethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl andhexyl. (1-5C)Alkyl groups are preferred, (1-4C)alkyl being the mostpreferred.

The term halogen means fluorine, chlorine, bromine or iodine.

The term (1-6C)alkoxy means an alkoxy group having 1-6 carbon atoms, thealkyl moiety having the same meaning as previously defined. (1-2C)Alkoxygroups are preferred.

The term (1-6C)alkoxycarbonyl means an alkoxycarbonyl group, the alkoxygroup of which contains 1-6 carbon atoms and has the same meaning aspreviously defined. (1-4C)Alkoxycarbonyl groups are preferred.

The term (1-4C)alkylsulfonyl means an alkylsulfonyl group, the alkylgroup of which contains 1-4 carbon atoms and has the same meaning aspreviously defined. (1-2C)Alkylsulfonyl groups are preferred.

The term (6-10C)aryl means an aromatic hydrocarbon group having 6-10carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl or indenyl,which may optionally be substituted with one or more substituentsselected from hydroxy, amino, halogen, nitro, trifluoromethyl, cyano or(1-4C)alkyl, the alkyl moiety having the same meaning as previouslydefined. The preferred aromatic hydrocarbon group is phenyl.

The term (6-10)arylsulfonyl means an arylsulfonyl group, the aryl groupof which contains 6-10 carbon atoms and has the same meaning aspreviously defined. Phenylsulfonyl is preferred.

The term (2-4C)alkenyl means a branched or unbranched alkenyl grouphaving 2-4 carbon atoms, such as ethenyl and 2-butenyl.

The term (2-4C)alkynyl means a branched or unbranched alkynyl grouphaving 2-4 carbon atoms, such as ethynyl and propynyl.

The term amino(1-4C)alkyl means an aminoalkyl group, the alkyl group ofwhich contains 1-4 carbon atoms and has the same meaning as previouslydefined. Amino(1-2C)alkyl groups are preferred.

The term hydroxy(1-4C)alkyl means a hydroxyalkyl group, the alkyl groupof which contains 1-4 carbon atoms and has the same meaning aspreviously defined. Hydroxy(1-2C)alkyl groups are preferred.

The term 1,4-bisaryl means two phenyl groups in which the second phenylgroup is connected to the 4-position of the first phenyl group.

The term carboxy(1-4C)alkyl means a carboxyalkyl group, the alkyl groupof which contains 1-4 carbon atoms and has the same meaning aspreviously defined. Carboxy(1-2C)alkyl groups are preferred.

The term (3-6C)cycloalkyl means a cycloalkyl group having 3-6 carbonatoms, being cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term pharmaceutically acceptable salt represents those salts whichare, within the scope of medical judgement, suitable for use in contactfor the tissues of humans and/or animals without undue toxicity,irritation, allergic response and the like, and are commensurate with areasonable benefit/risk ratio. Pharmaceutically acceptable salts arewell known in the art. They may be obtained during the final isolationand purification of the compounds of the invention, or separately byreacting the free base function with a suitable mineral acid such ashydrochloric acid, phosphoric acid, or sulfuric acid, or with an organicacid such as for example ascorbic acid, citric acid, tartaric acid,lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid,succinic acid, propionic acid, acetic acid, methanesulfonic acid, andthe like. The acid function can be reacted with an organic or a mineralbase, like sodium hydroxide, potassium hydroxide or lithium hydroxide.

For the purposes of the present invention, the term trans when namingfused polycyclic compounds is understood to mean that relativestereochemistry wherein the ring substituent in position 1 in Formula Iis located on the other side of said ring from the ring bond to anannulated ring system in position 14b. Consequently, the substituent inposition 1 is on the same side of the ring system as the bridgeheadhydrogen atom occupying position 14b. In addition, the use of the termtrans will be clear to those skilled in the art from the illustrationsin the various diagrams, figures and reaction schemes.

Prodrugs represent compounds which are rapidly transformed in vivo tothe parent compound of the above formula, for example by hydrolysis inblood.

The compounds of Formula I exist as mixtures of stereochemical isomers;preferred is absolute stereochemistry (1S,14bR).

Preferred compounds are those compounds wherein R2 is selected from thegroup consisting of H, halogen, NO₂, and NR11R12 wherein R11 and R12independently are selected from the group consisting of H,(1-6C)alkoxycarbonyl, (1-4C)alkylsulfonyl and (6-10C)arylsulfonyl.

Particularly preferred are the compounds according to Formula I whereinR1 and R5 are H and R3 and R4 are independently selected from H orhalogen.

X preferably is O, S or CH₂, more preferably O or CH₂. Other interestingcompounds are those compounds wherein R6 is H or C(Y)R15 and R15 is H or(1-4C)alkyl, preferably (1-2C)alkyl, the alkyl groups optionally beingsubstituted with one or more halogen atoms.

Also preferred are compounds wherein R2 is H, halogen or NO₂. Mostpreferred at R2 are H and F.

Most preferred compounds are those compounds wherein R11 is H and R12 is(1-6C)alkoxycarbonyl, (1-4C)alkylsulfonyl or (6-10C)arylsulfonyl.

Also highly preferred are compounds wherein R2 is H, R3 is halogen, R15is methyl, optionally substituted with 1-3 halogen atoms, and Y is O orS, more particularly those compounds wherein R4 is H and X is O.Compounds having some or more of the preferences identified abovecombined in the general Formula I are highly preferred.

Additional preferred compounds are those wherein R2 is H or halogen, R3and/or R4 are independently selected from the group consisting of H, CN,halogen, (2-4C)alkenyl and C(O)(1-4C)alkyl, and R5 and/or R10 areindependently selected from H or halogen.

More preferred are compounds wherein X is selected from the groupconsisting of O, S and NCH₃.

Also preferred are compounds wherein R8 and R9 are H.

Furthermore preferred are compounds wherein R6 is H or C(Y)R15 and R15is H or (1-4C)alkyl optionally substituted with one or more halogenatoms.

Also preferred are compounds wherein Y is O or S, and R15 is methyl,optionally substituted with one or more halogen atoms.

The sequences of steps to synthesize the compounds of the presentinvention are shown in Schemes I-XVIII. In each of the Schemes the Rgroups correspond to the substitution pattern noted in the Examples andto Formula I.

Tetracyclic templates (such as structure 11) were constructed by routinesynthetic methods as described in Scheme I. Nucleophilic aromaticsubstitution of 2-fluoro nitrophenyls with appropriately substitutedphenols, thiophenols or anilines provided the diaryl ethers, thioethersor amines 1, respectively. In the case of X=CH₂, structure 1 wascommercially available. Reduction of the nitro group with SnCl₂ yieldedthe aniline derivatives 2. Acylation of the aniline functionality with5-chlorovaleryl chloride yielded the amides 3. Subsequent ring closurewas accomplished by treatment of the amide with PPA at 150° C. Treatmentof imine structures 4 with sodium methoxide resulted in anintramolecular cyclization and afforded the tetracyclic systems S.Reaction of the enamine functionality with trichloroacetyl chlorideyielded the trichloroacetyl derivatives 6. The trichloroacetylfunctionality was transformed into methyl ester derivatives 7 ontreatment with sodium methoxide. Subsequent reduction of the alkenefunctionality of the unsaturated carboxylates 7 with borane gaveexclusively cis isomers such as structures 8. Epimerisation to the transisomers 9 was accomplished upon treatment of 8 with sodium methoxide.Saponification of the ester afforded the carboxylate 10 whichsubsequently was transformed via a classic Curtius reaction to an aminefunctionality resulting in thetrans-1-amino-tetrahydropyrido-dibenz(ox/othi/odi)azepine derivatives11. The racemic mixture was separated into its pure enantiomers viachiral HPLC (OJ column (25×0.46 cm)).

The tetracyclic compounds (11) were employed as starting materials inSchemes II and III. In Scheme II is depicted the acylation of the aminefunctionality of structure 11, which was accomplished via variousdifferent routine synthetic methods (i.e. acid chlorides, anhydrides,carboxylic acids with coupling reagents, or amidation). The resultingamide structures 12 were target of subsequent modification. Treatment ofthe amides such as structure 12 with phosphorous pentasulfide affordedthe thioamides 13.

Alkylation of the amide in 12 with alkylating agents in the presence ofsodium hydride afforded structures 14. Structures 15 have been preparedvia amidine formation of the amine functionality of 11 by treatment withnitrile derivatives such as trifluoroacetonitrile.

Scheme III describes the formation of the urethane structures 16starting from 11 via reaction with chloroformates in the presence ofsodium bicarbonate. Treatment of structure 11 with isothiocyanatesafforded the thiourea derivatives 17. Reductive alkylation of the aminefunctionality in structure 11 with aldehydes in the presence of sodiumtriacetoxyborohydride afforded structures 18. Alkylation of the aminefunctionality with 2-methoxyethyl bromide afforded structures 26.Structures 27 were obtained by treatment with t-butyl bromoacetate.

Direct electrophilic aromatic substitutions on core structures affordedvarious alternative aromatic substituted derivatives (Scheme IV-V).

In Scheme IV is described the chlorination of 12 wherein R3 is Cl withN-chlorosuccinimide in the presence of a catalytic amount of HCl; thisresulted in the formation of the two different substituted structures19A and 19B, which were easily separated. In contrast, bromination of 12with N-bromosuccinimide under identical conditions yielded only thecompound with structure 20. Reductive dehalogenation of the chlorocompound (12) was achieved by treatment with hydrogen in the presence ofPd/C and HCl to yield the hydro derivative 21. Nitration of structure 12with nitric acid gave completely selectively the mono-substitutedderivative 22.

Direct chlorination on structure 21 (Scheme V) with N-chlorosuccinimideafforded the two regioisomers 23A and 23B, two compounds which wereeasily separated by chromatographical methods.

As shown in Scheme VI reduction of the nitro functionality of structuressuch as 22 with SnCl₂.2H₂O in ethanol gave the aniline derivatives 24.Sulfonation or acylation of this aniline functionality afforded thesubstituted compounds such as structure 25,

As outlined in Scheme VII, treatment of dichloro compound 19B with K₂CO₃resulted in the formation of the corresponding amine 28 and subsequentformylation with ethyl formate afforded structure 29.

Schemes VIII and IX describe the synthesis of bromo derivatives 36 whereR4=Br.

Imine formation by treatment of a mixture of the amine and salicylaldehyde with p-toluenesulfonic acid and subsequent ring closure byetherification afforded tricyclic intermediates 31.

Scheme IX describes the sequences of steps to synthesize compounds 36starting from tricyclic intermediates such as compounds 31. Treatment oftricyclic imine 31 with glutaric anhydride afforded tetracycles 32. ACurtius rearrangement with DPPA and an alcohol resulted in the formationof urethane structures 33. Reduction of the amide functionality wasaccomplished by applying borane in THF. Treatment of urethane structures34 with HBr in acetic acid afforded amines 35. Acylation of the aminefunctionality with trifluoroacetic anhydride afforded the correspondingamides 36.

Bromo derivatives 36 were employed as starting materials in scheme X.Stille reactions afforded compounds with an acetyl (structures 37) or avinyl functionality (structures 39). Treatment of bromo derivatives 36with CuCN yielded the corresponding cyano compounds 38. Compound 40 wassynthesized by a Negishi reaction with a palladium catalyst andmethylzinc chloride. Treatment of bromo derivatives 36 with CuI andNaOMe yielded methoxy derivatives 41.

The synthesis of compounds 46 proceeded similar to the route describedfor bromo derivatives 36. The tricyclic intermediate 45 was synthesizedin a different manner than described in scheme XI. The synthesis startedwith an etherification followed by a reduction of the nitrofunctionality and a formylation of the amine 43. Treatment with PPA theneffected ring closure to tricyclic compound 45.

The bromo derivative 46 was used as starting material in scheme XIIwhere a vinyl (structure 49) and an acetyl derivative (structure 47)were formed by a Stille reaction. A nitrile functionality was introducedby treatment with CuCN. A benzylamine was introduced by a Buchwaldreaction; subsequent hydrogenation of this product generated the amine51. A reaction with propionyl chloride afforded the corresponding amide(structure 52).

The synthesis of derivatives with R5≠H is described in Schemes XIII andXIV. The tricyclic intermediate was obtained by imine formation andsubsequent ring closure through etherification.

Cyano derivative 56, methyl derivative 57 and dichloro compound 58 wereobtained by treatment of compound 55 with CuCN, methylzinc chloride orNCS, respectively, as was described in Scheme X.

The synthetic route towards fluoro derivatives 61 (R5 and/or R10=F) isshown in Scheme XV and is similar to the synthetic route towardsderivatives with R5 #H (Scheme XIII). In this case, ring closure byetherification was accomplished by using a microwave.

Derivatives with X=N-Me (structures 67, 68 and 69) were synthesizedaccording to Scheme XVI. Tricyclic intermediate 65 was synthesized by acoupling of 4-chloro-1-fluoro-2-nitrobenzene and N-methylaniline,followed by a reduction of the nitro functionality and a formylation ofthe amine. Ring closure towards intermediate 65 was accomplished bytreatment with PPA. The sequences of steps to synthesize compound 66from compound 65 are described in scheme IX. The amine functionality ofcompound 66 was acylated to yield amide 67 or alkylated to affordcompound 68. Subsequent saponification afforded compound 69.

The route towards derivatives with X═N—H proceeded via tricyclic amide72, which was obtained by an intramolecular condensation. Reduction withLiAlH₄ and subsequent oxidation with MnO₂ afforded tricyclicintermediate 74. The corresponding amide 75 was synthesized as describedin Scheme IX.

Application of 3-methyl glutaric anhydride in the formation oftetracyclic intermediate 78 and subsequent urethane formation resultedin a mixture of isomers 80, 81 and 82, as shown in Scheme XVIII.Treatment with HBr in acetic acid, followed by an acylation andseparation of the isomers, resulted in the formation of amides 86, 87and 88.

Methods to determine receptor binding as well as in vitro and in vivoassays to determine biological activity of the compounds are well known.In general, expressed receptor is treated with a compound of theinvention and binding or stimulation or inhibition of a functionalresponse is measured.

To measure a functional response, isolated DNA encoding the progesteronereceptor gene, preferably the human receptor, is expressed in suitablehost cells. Such a cell might be the Chinese Hamster Ovary (CHO) cell,but other cells are also suitable. Preferably the cells are of mammalianorigin.

Methods to construct recombinant progesterone receptor-expressing celllines are well known in the art (Sambrook et al., Molecular Cloning: aLaboratory Manual, Cold Spring Harbor Laboratory Press, Cold SpringHarbor, latest edition). Expression of receptor is attained byexpression of the DNA encoding the desired protein. Techniques forsite-directed mutagenesis, ligation of additional sequences, PCR, andconstruction of suitable expression systems are all, by now, well knownin the art. Portions or all of the DNA encoding the desi red protein canbe constructed synthetically using standard solid phase techniques,preferably to include restriction sites for ease of ligation. Suitablecontrol elements for transcription and translation of the includedcoding sequence can be provided through the DNA coding sequences. As iswell known, expression systems are now available which are compatiblewith a wide variety of hosts, including prokaryotic hosts such asbacteria and eukaryotic hosts such as yeast, plant cells, insect cells,mammalian cells, avian cells and the like.

Cells expressing the receptor are then contacted with a compound of theinvention to observe binding, or stimulation or inhibition of afunctional response.

Alternatively, isolated cytosol containing the expressed receptor may beused to measure binding of a compound of the invention.

For measurement of binding, radioactive or fluorescence-labelledcompounds may be used. As reference compound, the native hormone, orother compounds binding to the receptor, can be used. As an alternative,competition binding assays can be performed as well.

Another assay involves screening for progesterone receptor agonistcompounds of the invention by determining regulation of receptormediated natural target gene mRNA, i.e. genes regulated by the receptorthrough binding of the receptor in the promoter region of the gene. Thelevels of target gene mRNA will be reduced or increased, depending onthe inhibitory or stimulating effect of a compound of the invention uponbinding to the receptor.

In addition to direct measurement of mRNA levels in the exposed cells,cells can be used which in addition to transfection with receptorencoding DNA have also been transfected with a second DNA encoding areporter gene, the expression of which responds to binding of thereceptor towards responsive elements in the promoter of the particularreporter gene. Such responsive elements might be classical hormoneresponsive elements, well known in the art and described e.g., in Beato,M, Chalepakis, G, Schauer, M, Slater, E P (1989) J. Steroid Biochem. 5:737-47 or might be constructed in such a way that they are connected tonovel responsive elements. In general, reporter gene expression might becontrolled by any response element reacting to progesterone receptorbinding. Suitable reporter genes are e.g. LacZ, alkaline phosphatase,firefly luciferase and green fluorescence protein.

For selecting active agonist compounds on the progesterone receptor,testing at 10⁻⁵ M must result in an activity of more than 30% of themaximal activity when(16α)-16-ethyl-21-hydroxy-19-norpregn-4-ene-3,20-dione (Org 2058) isused as a reference. For selecting antagonist compounds on theprogesterone receptor, testing at 10⁻⁵ M must result in an activity ofmore than 10% of the maximal activity when(6β,11β,17β)-11-[4-(dimethylamino)phenyl]4′,5′-dihydro-6-methylspiro[estra-4,9-diene-17,2′(3′H)-furan]-3-one(Org 31710) is used as a reference. Another criterion might be the EC₅₀value, which must be <10⁻⁵ M, preferably <10⁻⁷ M.

The skilled artisan will recognize that desirable EC₅₀ values aredependent on the compound of the invention which is being tested. Forexample, a compound with an EC₅₀ which is less than 10⁻⁵ M is,generally, considered a candidate for drug selection. Preferably thisvalue is lower than 10⁻⁷ M. However, a compound which has a higher EC₅₀,but is selective for the particular receptor, may still be a candidatefor drug selection.

Basically any transactivation assay in mammalian cells (cell line orprimary culture), that can yield information about the possible receptoractivation can be used for the purpose of selecting potent ligands. Theadded value of using several cell systems, with cells which originatefrom different organs, will be that information on the potential tissuespecificity of the ligands is obtained. Examples of cells frequentlyused to this end are, besides CHO cells, a.o. T47D cells, MCF7 cells,ECC-1 cells, HeLa cells, primary cultures of endometrial cells, andpituitary cells.

The invention further resides in a pharmaceutical composition comprisinga compound having the general Formula I or a salt thereof.

Thus, the compounds according to the invention can be used in therapy.

The compounds of the present invention can be applied clinically inthose regimens where progestagens are used.

The invention therefore resides in the use of a compound having thegeneral Formula I for the manufacture of a medicament for modulatingprogesterone receptor mediated health conditions in women, more inparticular hormone dependent cancers such as breast, ovary and uteruscancer; endometriosis and fertility control. The invention also relatesto a treatment of the conditions identified above by administering acompound of the invention.

Suitable administration routes for the compounds of Formula I orpharmaceutically acceptable salts thereof, also referred to herein asthe active ingredient, are intramuscular injections, subcutaneousinjections, intravenous injections or intraperitoneal injections, oraland intranasal administration. Preferably, the compounds can beadministered orally. The exact dose and regimen of administration of theactive ingredient, or a pharmaceutical composition thereof, willnecessarily be dependent upon the therapeutic effect to be achieved(e.g. treatment of infertility; contraception, endometriosis) and mayvary with the particular compound, the route of administration, and theage and condition of the individual subject to whom the medicament is tobe administered.

In general, parenteral administration requires lower dosages than othermethods of administration which are more dependent upon adsorption.However, a dosage for humans preferably contains 0.0001-25 mg per kgbody weight. The desired dose may be presented as one dose or asmultiple subdoses administered at appropriate intervals throughout theday, or, in case of female recipients, as doses to be administered atappropriate (daily) intervals throughout the menstrual cycle. The dosageas well as the regimen of administration may differ between a female anda male recipient.

The present invention thus also relates to pharmaceutical compositionscomprising a compound according to Formula I in admixture withpharmaceutically acceptable auxiliaries, and optionally othertherapeutic agents. The auxiliaries must be “acceptable” in the sense ofbeing compatible with the other ingredients of the composition and notdeleterious to the recipients thereof.

Pharmaceutical compositions include those suitable for oral, rectal,nasal, top ical (including transdermal, buccal and sublingual), vaginalor parenteral (including subcutaneous, intramuscular, intravenous andintradermal) administration or administration via an implant. Thecompositions may be prepared by any method well known in the art ofpharmacy, for example, using methods such as those described in Gennaroet al., Remington's Pharmaceutical Sciences (18th ed., Mack Publishingcompany, 1990, see especially Part 8: Pharmaceutical Preparations andTheir Manufacture).

Such methods include the step of bringing in association the activeingredient with any auxiliary agent. The auxiliary agent(s), also namedaccessory ingredients, include those conventional in the art (Gennaro,supra), such as, fillers, binders, diluents, disintegrants, lubricants,colorants, flavouring agents and wetting agents.

Pharmaceutical compositions suitable for oral administration may bepresented as discrete dosage units such as pills, tablets or capsules,or as a powder or granules, or as a solution or suspension. The activeingredient may also be presented as a bolus or paste. The compositionscan further be processed into a suppository or enema for rectaladministration.

The invention further includes a pharmaceutical composition, ashereinbefore described, in combination with packaging material,including instructions for the use of the composition for the use ashereinbefore described.

For parenteral administration, suitable compositions include aqueous andnon-aqueous sterile injection. The compositions may be presented inunit-dose or multi-dose containers, for example sealed vials andampoules, and may be stored in a freeze-dried (lyophilised) conditionrequiring only the addition of sterile liquid carrier, for example,water prior to use.

Compositions or formulations suitable for administration by nasalinhalation include fine dusts or mists which may be generated by meansof metered dose pressurized aerosols, nebulisers or insufflators.

The derivatives of the invention can also be administered in the form ofdevices, consisting of a core of active material, encased by a releaserate-regulating membrane. Such implants are to be applied subcutaneouslyor locally, and will release the active ingredient at an approximatelyconstant rate over relatively large periods of time, for instance fromweeks to years. Methods for the preparation of implantablepharmaceutical devices as such are known in the art, for example asdescribed in European Patent 0,303,306 (AKZO N.V.).

The invention is illustrated by the foll owing examples.

EXAMPLES Example 1Trans-7-Fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(Structure 11 of Scheme I, where R1=H, R2=H, R3=F, R4=H, R5=H, R6=H,R7=H, X=O) 5-Fluoro-2-phenoxynitrobenzene

Cs₂CO₃ (12.1 g, 62.9 mmol) was added to a solution of phenol (5.9 g,62.9 mmol) in 400 mL of THF under N₂. After stirring for 15 min.2,5-difluoronitrobenzene (6.82 mL, 62.9 mmol) in 50 mL of THF was added.The resulting mixture was heated to 40° C. for 25 h. Reaction wasfollowed by HPLC to detect disappearance of 2,5-difluoronitrobenzene.Water and ethyl acetate were added, followed by extraction with ethylacetate (2×). The combined organic layers were successively washed withsaturated aq. sodium bicarbonate (3×), water and brine, dried (Na₂SO₄)and evaporated. The crude compound was chromatographed on silica toremove excess of phenol. Elution with toluene/ethyl acetate 95:5 gavethe title compound (12.6 g, 86%). Data: (m/z)=234 (M+H)⁺.

5-Fluoro-2-phenoxyaniline

General Method 1: Reduction of a Nitro Compound of Structure 1 to anAniline of Structure 2.

SnCl₂.2H₂O (88.0 g, 390 mmol) was added to a solution of5-Fluoro-2-phenoxynitrobenzene (22.3 g, 95.7 mmol) in 450 mL of ethanolunder N₂. The resulting mixture was stirred at 40° C. for 30 min. andadditionally under cooling for 2 h. Ethanol was removed by evaporationunder reduced pressure and 300 mL of ethyl acetate was added. Theorganic layer was washed with water and cold 1N NaOH. The emulsion wasfiltered over decalite, washed with water, extracted with ethyl acetate,dried (Na₂SO4), and evaporated to give the crude compound as a darkbrown oil (19.6 g, 100%). Data: (m/z)=204 (M+H)⁺.

5-Chloro-N-(5-fluoro-2-phenoxyphenyl)pentanamide

General Method 2: Acylation of an Aniline of Structure 2 to an Amide ofStructure 3.

A solution of 5-chloropentanoyl chloride (13.0 mL, 100 mmol) in 13 mLCH₂Cl₂ was added in 30 minutes to a solution of5-fluoro-2-phenoxyaniline (19.6 g, 95.7 mmol) in 88 mL of CH₂Cl₂ and 7mL of pyridine at <25° C. After the mixture had been stirred for 1 h atroom temperature 100 mL of ice-water was added at 0° C. After 18 hstirring at room temperature the two layers were separated. The organiclayer was washed with cold 2N NaOH and water, dried (Na₂SO4) andevaporated to give the crude compound as a brown oil (31.0 g, 100%).Data: (m/z)=322 (M+H)⁺.

8-Fluoro-11-(4-chlorobutyl)dibenz[b,f][1,4]oxazepine

General Method 3: Ring Closure of an Amide of Structure 3 to an Imine ofStructure 4.

PPA (190 g, 84%) was added to a solution of5-chloro-N-(5-fluoro-2-phenoxyphenyl)pentanamide (31.0 g, 95.7 mmol).The resulting mixture was stirred at 150° C. for 2.5 h and subsequentlycooled to 50° C. 500 mL of ethyl acetate and 300 mL of ice-water wereadded. The mixture was stirred for 1 h. The organic layer was washedwith cold 1N NaOH and water, dried (Na₂SO₄) and evaporated to give thecrude compound as a black oil (26.3 g, 90%). Data: (m/z)=304 (M+H)⁺.

7-Fluoro-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine

General Method 4: Ring Closure of an Imine of Structure 4 to aTetracycle of Structure 5.

A solution of 8-fluoro-11-(4-chlorobutyl)dibenz[b,f][1,4]oxazepine (26.3g, 86.6 mmol) in 45 mL of methanol was added to a solution of sodiummethoxide (9.6 g, 177 mmol) in 115 mL of methanol under N₂. Theresulting mixture was heated to reflux for 5 h, cooled to roomtemperature and stirred overnight. Water and CH₂Cl₂ were added and themixture was poured into 500 mL of water and extracted with CH₂Cl₂. Theorganic layer was washed with water, dried (Na₂SO₄) and evaporated, andthe crude compound was chromatographed on silica. Elution with toluenegave the title compound as a brown oil (16.5 g, 77%). Data: (m/z)=268(M+H)⁺.

7-Fluoro-1-(trichloroacetyl)-3,4-dihydro-2H-d]dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine

General Method 5: Conversion of an Enamine of Structure 5 to aTrichloroacetyl Derivative of Structure 6.

Trichloroacetyl chloride (8.75 mL, 78.5 mmol) was added to a solution of7-fluoro-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine (16.5 g,61.9 mmol) in 125 mL of toluene under N₂. After stirring for 15 min.triethylamine (7.7 mL) was added over 15 min. The resulting brownsuspension was heated to 120° C. for 75 min. After cooling to 5° C. 100mL of ice-water was added. After stirring for 1 h the mixture was pouredinto 500 mL water and extracted with ethyl acetate. The organic layerwas washed with cold saturated aq. sodium bicarbonate and water, dried(Na₂SO₄) and evaporated to give the crude compound as a black foam (19.1g, 75%). Data: (m/z)=412 (M+H)⁺.

Methyl7-fluoro-3,4-dihydro-2H-d]dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylate

General Method 6: Conversion of a Trichloroacetyl Compound of Structure6 to a Methyl Ester of Structure 7.

A solution of sodium methoxide (7.64 g, 141.6 mmol) in 60 mL of methanolwas added to a suspension of7-fluoro-1-(trichloroacetyl)-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine(19.1 g, 46.4 mmol) in 60 mL of methanol. The resulting mixture wasstirred for 30 min. at room temperature and heated to reflux for 1 h.After cooling to room temperature the mixture was poured into 700 mL ofice-water and extracted with CH₂Cl₂. The organic layer was washed withwater, dried (Na₂SO₄) and evaporated to give the title compound as ablack foam (13.9 g, 92%). Data: (m/z)=326 (M+H)⁺.

Methylcis-7-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f][pyrido[1,2-d][1,4]oxazepine-1-carboxylate

General Method 7: Reduction of an Unsaturated Carboxylate of Structure 7to a Saturated Carboxylate of Structure 8.

BH₃-THF complex (1M, 40 mL, 40.0 mmol) was added in 45 min. to asolution of methyl7-fluoro-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylate(14.0 g, 42.8 mmol) in 84 mL of THF under N2 (T<5° C.). The resultingmixture was stirred for 105 min. at 20° C. After cooling to 0° C. 20 mLof acetic acid was added in 2 h. The reaction mixture was poured into500 mL of ice-water, extracted with CH₂Cl₂, washed with water, dried(Na₂SO₄) and evaporated. The crude product was chromatographed onsilica. Elution with heptane/ethyl acetate 7:3 gave the title compoundas a light brown foam (10.0 g, 71%). Data: (m/z)=328 (M+H)⁺.

Methyltrans-7-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylate

General Method 8: Epimerisation of cis-Carboxylate of Structure 8 to atrans-Carboxylate of Structure 9.

Sodium methoxide (1.00 g, 1.85 mol) was added to a suspension of methylcis-7-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f][pyrido[1,2-d][1,4]oxazepine-1-carboxylate(10.0 g, 30.6 mmol) in 100 mL of methanol under N₂. The resultingmixture was heated to reflux for 4.5 h. After cooling the clear brownsolution was poured into 700 mL of ice-water and extracted with CH₂Cl₂.The organic layer was washed with water, dried (Na₂SO₄) and evaporatedto give the title compound (9.1 g, 91%). Data: (m/z)=328 (M+H)⁺.

trans-3-Fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylicAcid

General Method 9: Saponification of a Carboxylate of Structure 9 to aCarboxylic Acid of Structure 10.

65 mL of 2N NaOH was added to a solution of methyltrans-7-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylate(9.10 g, 27.8 mmol) in 280 mL of dioxane and 110 mL of water. Theresulting mixture was heated to 70° C. for 2 h. The cooled mixture waspoured into 1.5 L of ice-water and 100 mL of 2N HCl and extracted withCH₂Cl₂ (3×). The organic layer was washed with water, dried (Na₂SO₄) andevaporated. Crystallisation from CH₂Cl₂/ether 1:3 gave the titlecompound (5.3 g, 61%). Data: (m/z)=314 (M+H)⁺.

trans-7-Fluoro-2,3,4,14b-tetrahydro-1H-d]-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(Structure 11 of Scheme 1, where R1=H, R2=H, R3=F, R4=H, R5=H, R6=H,R7=H, X=O)

General Method 10: Amination of Carboxylic Acid of Structure 10 to anAmine of Structure 11.

2.60 mL of triethylamine was added in 5 minutes at 0° C. under N₂ to asuspension oftrans-7-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylicAcid (4.0 g, 12.8 mmol) in 30 mL of acetone and 1 mL of water.Additionally 1.80 mL of ethyl chloroformate was added and the mixturewas stirred at 0° C. for 30 min. Sodium azide (1.65 g, 26.3 mmol) in 8mL of water was added to the resulting emulsion and stirring wascontinued for 2.5 h at 0° C. The mixture was poured into 500 mL of waterand extracted with CH₂Cl₂. The organic layer was washed with water,dried (Na₂SO₄) and evaporated to give the crude compound. This crudeproduct was dissolved in 90 mL of 1,2-dichloropropane and heated to 100°C. for 4 h. The mixture was then evaporated under reduced pressure. Theresidue was dissolved in 45 mL of methoxyethanol. A solution of sodiumhydroxide (2.72 g, 84.7 mmol) in 6 mL of water was added. The resultingmixture was heated to 120° C. for 2.5 h after which it was cooled andpoured into 400 mL of ice-water. The water layer was extracted withCH₂Cl₂ and the organic layer was washed with water, dried (Na₂SO₄),evaporated and chromatographed on alumina. Elution with toluene/ethylacetate 3:7 gave the title compound as a brown oil (1.45 g, 34%). Data:(m/z)=285 (M+H)⁺.

Example 2trans-7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]thiazepine-1-amine(Structure 11 of Scheme I, where R1=H, R2=H, R3=Cl, R4=H, R5=H, R6=H,R7=H, X=S) 5-Chloro-2-(phenylthio)aniline

This compound was prepared by General Method 1 at room temperature toafford 5-chloro-2-(phenylthio)aniline (6.8 g, 77%). Data: (m/z)=236(M+H)⁺.

5-Chloro-N-[5-chloro-2-(phenylthio)phenyl]pentanamide

This compound was prepared by General Method 2 to afford5-chloro-N-[5-chloro-2-(phenylthio)phenyl]pentanamide (11.0 g, 100%).Data: (m/z)=354 (M+H)⁺.

8-Chloro-11-(4-chlorobutyl)dibenzo[b,f][1,4]thiazepine

This compound was prepared by General Method 3 to afford8-chloro-11-(4-chlorobutyl)dibenzo[b,f][1,4]thiazepine as a black tar(4.0 g, 45%). Data: (m/z)=338 (M+H)⁺.

7-Chloro-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]thiazepine

This compound was prepared by General Method 4, followed bychromatography on silica. Elution with toluene gave7-chloro-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]thiazepine as ared-brown oil (1.2 g, 47%). Data: (m/z)=300 (M+H)⁺.

7-Chloro-1-(trichloroacetyl)-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]thiazepine

This compound was prepared by General Method 5 to afford7-chloro-1-(trichloroacetyl)-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]thiazepineas a black tar (1.6 g, 93%). Data: (m/z)=446 (M+H)⁺.

Methyl7-chloro-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]thiazepine-1-carboxylate

This compound was prepared by General Method 6 to afford methyl7-chloro-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]thiazepine-1-carboxylateas a black foam (1.2 g, 94%).

Methylcis-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]thiazepine-1-carboxylate

This compound was prepared by General Method 7 to afford methylcis-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]thiazepine-1-carboxylateas a brown foam (1.0 g, 100%). Data: (m/z)=360 (M+H)⁺.

Methyltrans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]thiazepine-1-carboxylate

This compound was prepared by General Method 8 to afford methyltrans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]thiazepine-1-carboxylate(0.77 g, 73%). Data: (m/z)=360 (M+H)⁺.

trans-7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]thiazepine-1-carboxylicAcid

This compound was prepared by General Method 9 to affordtrans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]thiazepine-1-carboxylicacid (0.24 g, 32%). Data: (m/z)=346 (M+H)⁺.

trans-7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]thiazepine-1-amine(Structure 11 of Scheme I, where R1=H, R2=H, R3=Cl, R4=H, R5=H, R6=H,R7=H, X=S)

This compound was prepared by General Method 10 to affordtrans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]thiazepine-1-amineas a brown solid (165 mg, 75%). Data: (m/z)=317 (M+H)⁺.

Example 3trans-7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(Structure 11 of Scheme I, where R1=H, R2=H, R3=Cl, R4=H, R5=H, X=O)5-Chloro-N-(5-chloro-2-phenoxyphenyl)pentanamide

This compound was prepared by General Method 2 to afford5-chloro-N-(5-chloro-2-phenoxyphenyl)pentanamide as a brown oil (24.1 g,100%). Data: ¹H-NMR (400 MHz, CDCl₃) 1.83 (m, 4H), 2.40 (t, J=7.0, 2H),3.54 (t, J=7.0, 2H), 6.76 (d, J=8.0, 1H), 6.97 (dd, J=8.0, 2.0, 1H),6.99 (s, 1H), 7.02 (s, 1H), 7.17 (t, J=8.0, 1H, 7.37 (d, J=8.0, 1H),7.39 (d, J=8.0, 1H), 7.72 (br, 1H), 8.54 (d, J=2.0, 1H). (m/z)=338(M+H)⁺.

8-Chloro-11-(4-chlorobutyl)dibenz[b,f][1,4]oxazepine

This compound was prepared by General Method 3 to afford8-chloro-11-(4-chlorobutyl)dibenz[b,f][1,4]oxazepine as a thickbrown-greenish oil (21.6 g, 94%). Data: ¹H-NMR (400 MHz, CDCl₃) 1.90 (m,4H), 2.96 (t, J=8.0, 2H), 3.58 (t, J=8.0, 2H), 7.04-7.48 (7 arH).(m/z)=320 (M+H)⁺.

7-Chloro-3,4-dihydro-2H-dibenz[b,f]pyrido[1,2-d][1,4]oxazepine

This compound was prepared by General Method 4, followed bychromatography on alumina. Elution with toluene gave7-chloro-3,4-dihydro-2H-dibenz[b,f]pyrido[1,2-d][1,4]oxazepine as a darkbrown oil (3.92 g, 83%). Data: ¹H-NMR (400 MHz, CDCl₃) 2.06 (dt, J=16.0,8.0, 2H), 2.32 (m, 2H), 3.69 (t, J=8.0, 2H), 4.87 (t, J=4.0, 1H), 6.73(dd, J=8.0, 3.0, 1H), 6.90 (d, J=3.0, 1H), 7.02 (d, J=8.0, 1H), 7.09 (m,2H), 7.22 (m, 1H), 7.36 (dd, J=8.0, 2.0, 1H). (m/z)=284 (M+H)⁺.

7-Chloro-1-(trichloroacetyl)-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine

This compound was prepared by General Method 5 to afford7-chloro-1-(trichloroacetyl)-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine]as a black tar (5.70 g, >100% crude). Data: ¹H-NMR (400 MHz, CDCl₃) 2.19(dt, J=16.0, 8.0, 2H), 2.95 (m, 2H), 3.90 (m, 2H), 6.96 (dd, J=8.0, 3.0,1H), 7.04-7.37 (7 arH). (m/z)=430 (M+H)⁺.

Methyl7-chloro-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylate

This compound was prepared by General Method 6 followed bychromatography on silica. Elution with toluene/ethyl acetate 9:1 gavemethyl7-chloro-3,4-dihydro-2H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylate](2.75 g, 65%). Data: ¹H-NMR (400 MHz, CDCl₃) 2.11 (dt, J=16.0, 8.0, 2H),2.65 (m, 2H), 3.38 (s, 3H), 3.82 (m, 2H), 6.88 (dd, J=8.0, 3.0, 1H),7.06 (m, 3H), 7.14 (d, J=8.0, 1H), 7.23 (dd, J=8.0, 2.0, 1H), 7.30 (dt,J=8.0, 2.0, 1H). (m/z)=342 (M+H)⁺.

Methylcis-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylate

This compound was prepared by General Method 7 to afford methylcis-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-carboxylate]as a yellow-brown foam (10.2 g, 100%). Data: ¹H-NMR (400 MHz, CDCl₃)2.27 (m, 4H), 3.02 (dt, J=12.0, 4.0, 1H), 3.16 (m, 2H), 3.53 (s, 3H),5.06 br, 1H), 6.75 (dd, J=8.0, 3.0, 1H), 6.90 (d, J=3.0, 1H), 7.00 (d,J=8.0, 1H), 7.05 (dt, J=8.0, 2.0, 1H), 7.17 (dt, J=8.0, 2.0, 2H), 7.20(dt, J=8.0, 2.0, 1H). (m/z)=344 (M+H)⁺.

Methyltrans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylate

This compound was prepared by General Method 8 to afford methyltrans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylate(9.5 g, 93%). Data: (m/z)=344 (M+H)⁺.

trans-7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylicAcid

This compound was prepared by General Method 9. Crystallisation fromCH₂Cl₂/ether 1:3 gavetrans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylicacid] (3.89 g, 51%) Data: (m/z)=302 (M+H)⁺.

trans-7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(Structure 11 of Scheme I, where R1=H, R2=H, R3=Cl, R4=H, R5=H, X=O)

This compound was prepared by General Method 10. Crystallisation fromether gavetrans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amineas an off-white solid (2.97 g, 68%). Data: (m/z)=301 (M+H)⁺.

Example 4trans-7-Chloro-1,2,3,4,10,14b-hexahydro-dibenzo[c,f]pyrido[1,2-a]azepine-1-amine(Structure 11 of Scheme I, where R1=H, R2=H, R3=Cl, R4=H, R5=H, R6=H,R7=H, X=CH₂) 5-Chloro-N-[5-chloro-2-(phenylmethyl)phenyl]pentanamide

This compound was prepared by General Method 2 to afford5-chloro-N-[5-chloro-2-(phenylmethyl)phenyl]pentanamide as an off-whitesolid (2.90 g, 100%). Data: (m/z)=336 (M+H)⁺.

3-Chloro-6-(4-chlorobutyl)-11H-dibenz[b,e]azepine

This compound was prepared by General Method 3 to afford3-chloro-6-(4-chlorobutyl)-11H-dibenz[b,e]azepine (Scheme I, structure 4wherein R1=R2=R4=R5=H, R3=Cl, X=CH₂ and n=4) as a black tar (2.60 g,97%). Data: (m/z)=318 (M+H)⁺.

7-Chloro-2,3,4,10-tetrahydrodibenzo[c,f]pyrido[1,2-a]azepine

This compound was prepared by General Method 4, followed bychromatography on silica. Elution with toluene gave7-chloro-2,3,4,10-tetrahydrodibenzo[c,f]pyrido[1,2-a]azepine as aorange-brown oil (0.89 g, 39%). Data: (m/z)=282 (M+H)⁺.

7-Chloro-1-(trichloroacetyl)-2,3,4,10-tetrahydrodibenzo[c,f]pyrido[1,2-a]azepine

This compound was prepared by General Method 5 to afford7-chloro-1-(trichloroacetyl)-2,3,4,10-tetrahydrodibenzo[c,f]pyrido[1,2-a]azepineas a dark brown foam (1.34 g, 99%).

Methyl7-chloro-2,3,4,10-tetrahydrodibenzo[c,f]pyrido[1,2-a]azepine-1-carboxylate

This compound was prepared by General Method 6 to afford methyl7-chloro-2,3,4,10-tetrahydrodibenzo[c,f]pyrido[1,2-a]azepine-1-carboxylateas a dark brown foam (1.01 g, 95%). Data: (m/z)=340 (M+H)⁺.

Methylcis-7-chloro-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-1-carboxylate

This compound was prepared by General Method 7 to afford methylcis-7-chloro-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-1-carboxylateas a dark brown foam (1.00 g, 98%). Data: (m/z)=342 (M+H)⁺.

Methyltrans-7-chloro-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-1-carboxylate

This compound was prepared by General Method 8 to afford methyltrans-7-chloro-1,2,3,4,10,14b-hexahydro-dibenzo[c,f]pyrido[1,2-a]azepine-1-carboxylate(0.93 g, 93%).

trans-7-Chloro-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-1-carboxylicAcid

This compound was prepared by General Method 9. Crystallisation fromCH₂Cl₂/ether 1:3 gavetrans-7-chloro-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-1-carboxylicacid (3.89 g, 51%) Data: (m/z)=302 (M+H)⁺.

trans-7-Chloro-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-1-amine(Structure 11 of Scheme I, where R1=H, R2=H, R3=Cl, R4=H, R5=H, R6=H,R7=H, X=CH2)

This compound was prepared by General Method 10 to affordtrans-7-chloro-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-1-amine(104 mg, 86%). Data: (m/z)=299 (M+H)⁺.

Example 5trans-2,2,2-Trifluoro-N-(7-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)acetamide

(Structure 12 of Scheme II, where R1=H, R2=H, R3=F, R4=H, R5=H, R15=CF₃,X=O)

General Method 11: N-acylation of an Amine of Structure 11 to aTrifluoro Amide of Structure 12.

Trifluoroacetic anhydride (1 mL) was added totrans-7-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(0.6 g, 2.1 mmol) in 5 mL CH₂Cl₂ and 2 mL of pyridine. The resultingsuspension was stirred for 18 h at room temperature. The brown solutionwas poured into 100 mL of ice-water and extracted with CH₂Cl₂. Theorganic layer was washed with water, dried (Na₂SO₄) and evaporated.Diethyl ether was added to the resulting solid and heated to reflux for30 min. The residue was dissolved in CH₂Cl₂ and heated to reflux for 30min. The precipitate was filtered off, washed with CH₂Cl₂ and dried togivetrans-2,2,2-trifluoro-N-(7-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)acetamideas an off-white solid (0.2 g, 25.6%). Data: (m/z)=381 (M+H)⁺.

Example 6trans-2,2,2-Trifluoro-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]thiazepin-1-yl)acetamide(Structure 13 of Scheme II, where R1=H, R2=H, R3=Cl, R4=H, R5=H,R15=CF₃, X=S)

This compound was prepared by General Method 11, followed bychromatography on silica. Elution with toluene→toluene/ethyl acetate95:5 followed by crystallisation from ether, which gavetrans-2,2,2-trifluoro-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]thiazepin-1-yl)acetamideas an off-white solid (3.0 mg, 12%). Data: (m/z)=413 (M+H)⁺.

Example 7trans-N-(7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2-2-2-trifluoroacetamide(Structure 12 of Scheme II, where R1=H, R2=H, R3=Cl, R4=H, R5=H,R15=CF₃, X=O)

Successively, ethyl trifluoroacetate (1.41 mL, 11.8 mmol) andtriethylamine (628 μL, 4.5 mmol) were added totrans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(291 mg, 0.97 mmol) in 11.8 mL of methanol. The resulting mixture washeated to 50° C. for 18 h. A precipitate was formed. The mixture wasevaporated under reduced pressure to remove volatile reagents and 5 mLof methanol was added. After 30 min. stirring the precipitate wasfiltered off, washed with diethyl ether and dried to givetrans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamideas an off-white solid (330 mg, 86%). Data: ¹H-NMR (400 MHz, CDCl₃) 1.85(m, 2H), 2.26 (m, 1H), 3.12 (m, 1H), 3.20 (m, 1H), 3.62 (dt, J=12.0,4.0, 1H), 4.38 (d, J=8.0, 1H), 4.68 (m, 1H), 6.76 (dd, J=8.0, 3.0, 1H),6.93 (d, J=3.0, 1H), 7.04 (d, J=8.0, 1H), 7.08 (dt, J=8.0, 2.0, 1H),7.17 (dd, J=8.0, 2.0, 2H), 7.29 (dt, J=8.0, 2.0, 1H). (m/z)=397 (M+H)⁺.

Example 8trans-N-(7-Chloro-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-1-yl)-2,2,2-trifluoroacetamide(Structure 12 of Scheme II, where R1=H, R2=H, R3=Cl, R4=H, R5=H,R15=CF₃, X=CH₂)

This compound was prepared by General Method 11, followed bychromatography on silica. Elution with toluene→toluene/ethyl acetate95:5 gavetrans-N-(7-chloro-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-1-yl)-2,2,2-trifluoroacetamide(34.0 mg, 12%). Data: (m/z)=395 (M+H)⁺.

Example 9trans-N-(1,2,3,4,10,14b-Hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-1-yl)-2,2,2-trifluoroacetamide(Structure 12 of Scheme II, where R1=H, R2=H, R3=H, R4=H, R5=H, R15=CF₃,X=—(CH₂)

This compound was prepared by General Method 11 starting fromtrans-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepine-1-aminemaleate, followed by chromatography on silica. Elution withtoluene→toluene/ethyl acetate 9:1 gavetrans-N-(1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrido[1,2-a]azepin-1-yl)-2,2,2-trifluoroacetamide(3.6 mg, 76%). Data: (m/z)=359 (M+H)⁺.

Example 10trans-N-(7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin1-yl)acetamide(Structure 12 of Scheme II, where R1=R2=H, R3=Cl, R4=R5=H, R15=CH₃, X=O)

trans-7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-aminemaleate (10 mg, 0.02 mmol), 50 μL of pyridine, and 25 μL of aceticanhydride in 1 mL of CH₂Cl₂ were stirred for 18 h at room temperature.The mixture was washed with 5% aqueous sodium bicarbonate and H₂O, dried(Na₂SO₄) and evaporated to givetrans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin1-yl)acetamide(9.0 mg, 65%). Data: (m/z)=343 (M+H)⁺.

Example 11trans-N-(7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2-fluoroacetamide(Structure 12 of Scheme II, where R1=R2=H, R3=Cl, R4=R5=H, R15=CH₂F,X=O)

trans-7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(10 mg, 0.03 mmol) was dissolved in 1 mL of ethyl fluoroacetate. Theresulting mixture was heated to reflux for 2 h. Evaporation followed bycrystallisation from methanol gavetrans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2-fluoroacetamide(4.7 mg, 39%). Data: (m/z)=361 (M+H)⁺.

Example 12trans-N-(7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-4-phenylbenzamide(Structure 12 of Scheme II, where R1=R2=H, R3=Cl, R4=R5=H, R15=C₆H₄C₆H₅,X=O)

General Method 12: N-acylation of an Amine of Structure 11 to an Amideof Structure 12.

DIPEA (18.6 μL, 0.14 mmol) and 4-phenylbenzoyl chloride (15.2 mg, 0.07mmol) were added to a solution oftrans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-aminemaleate (9.6 mg, 0.02 mmol) in 1 mL of CH₂Cl₂. The resulting mixture wasstirred for 18 h at room temperature. The organic layer was washed with5% aqueous sodium bicarbonate and H 20, dried (Na₂SO₄) and evaporated.Additional chromatography on silica (elution with toluene/ethyl acetate9:1→toluene/ethyl acetate 1:1) gavetrans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-4-phenylbenzamide(4.6 mg, 44%). Data: (m/z)=350 (M+H)⁺.

The following amides listed in Table 1 were prepared essentially byGeneral Method 12, using the appropriate starting materials. For Example15 triethylamine was used instead of DIPEA and the compound wascrystallised from diethyl ether. TABLE 1 yield Ex R1 R2 R3 R4 R5 R6 R7R15 X (m/z) (%) 13 H H Cl H H C(O)R15 H CHF₂ O 379 35 14 H H Cl H HC(O)R15 H CH₂Cl O 377 52 15 H H Cl H H C(O)R15 H CH₂Br O 422 50

Example 16trans-2-Amino-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)acetamide(Structure 12 of Scheme II, where R1=R2=H, R3=Cl, R4=R5=H, R15=CH₂NH₂,X=O)Trans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)amino]carbonyl]methyl]carbamicAcid 1,1-dimethylethyl Ester

General Method 13: N-acylation of an Amine of Structure 11 to an Amideof Structure 12.

DIPEA was added (pH=9) totrans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(10 mg, 0.03 mmol) in 1 mL of CH₂Cl₂ with HATU (12.5 mg, 0.03 mmol) andBoc-Gly-OH (10.3 mg, 0.03 mmol). The resulting mixture was stirred for 3h, washed with 5% aqueous sodium bicarbonate and H₂O, dried (Na₂SO₄) andevaporated to give[[[(trans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)amino]carbonyl]methyl]carbamicAcid 1,1-dimethylethyl Ester (14.3 mg, 100%). Data: (m/z)=405 (M+H)⁺.

trans-2-Amino-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)acetamide(Structure 12 of Scheme II, where R1=R2=H, R3=Cl, R4=R5=H, R15=CH₂NH₂,X=O)

trans-7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)amino]carbonyl]methyl]carbamicacid 1,1-dimethylethyl ester (10 mg, 0.02 mmol) in 2 mL of ethyl acetatewas purged with HCl gas at 0° C. for 2 h. The mixture was evaporatedunder reduced pressure to givetrans-2-amino-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)acetamide(9.2 mg, 100%). Data: (m/z)=358 (M+H)⁺.

Example 17trans-4-[(7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)amino]-2,2,3,3-tetrafluoro-4-oxobutanoicAcid (Structure 12 of Scheme II, where R1=R2=H, R3=Cl, R4=R5=H,R15=CF₂CF₂C(O)OH, X=O)

Tetrafluorosuccinic anhydride (5.35 μL, 0.05 mmol) was added totrans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(10 mg, 0.03 mmol) in 1 mL of dioxane. The resulting mixture was stirredat room temperature for 30 minutes. Dioxane was removed by evaporationunder reduced pressure and ethyl acetate and 2% citric acid were added.The organic layer was washed with brine, dried (Na₂SO₄) and evaporatedto givetrans-4-[(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)amino]-2,2,3,3-tetrafluoro-4-oxobutanoicacid (10.6 mg, 51%). Data: (m/z)=472 (M+H)⁺.

Example 18trans-N-(7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)methanethioamide(Structure 13 of Scheme II, where R1=R2=H, R3=Cl, R4=R5=H, R15=H, X=O)trans-N-(7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)formamide

trans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(10 mg, 0.03 mmol) was dissolved in 1 mL of ethyl formate. The resultingmixture was heated to reflux for 18 h. The cooled mixture was evaporatedto givetrans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)formamide(12.0 mg, 100%). Data: (m/z)=329 (M+H)⁺.

trans-N-(7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)methanethioamide(Structure 13 of Scheme II, where R1=R2=H, R3=Cl, R4=R5=H, R15=H, X=O)

General Method 14: Sulfonylation of an Amide of Structure 12 to aThioamide of Structure 13.

Phosphorus pentasulfide (5 mg, 0.01 mmol) was added totrans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)formamide(5 mg, 0.015 mmol) in dioxane. The resulting mixture was heated toreflux for 3 h. After evaporation under reduced pressure the crudecompound was chromatographed on silica. Elution with toluene/ethylacetate 85:15 gavetrans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)methanethioamide(2.8 mg, 51%). Data: (m/z)=345 (M+H)⁺.

The following thioamides listed in Table 2 were prepared essentially byGeneral Method 14, using the appropriate starting materials. They arereferred to as examples 19 through 27. TABLE 2 Ex R1 R2 R3 R4 R5 R6 R7R15 X (m/z) Yield (%) 19 H H Cl H H C(S)R15 H CF₃ O 413 98 20 H H Cl H HC(S)R15 H CF₃ CH₂ 411 62 21 H H Cl H H C(S)R15 H CH₃ O 359 11 22 H H ClH H C(S)R15 H CH₂F O 378 63 23 H H Cl H H C(S)R15 H CHF₂ O 395 80 24 H HCl H H C(S)R15 CH₃ CF₃ O 428 49 25 H H H H H C(S)R15 H CF₃ O 379 24 26 HH Cl Cl H C(S)R15 H CF₃ O 448 47 27 H H Cl H H C(S)R15 H CH₂NH₂ O 374 75

Example 28trans-N-(7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoro-N-methylacetamide(Structure 14 of Scheme II, where R1=R2=Cl, R4=R5=H, R7=CH₃, R15=CF₃,X=O)

Sodium hydride (1.6 mg, 60% in oil) was added totrans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(15 mg, 0.04 mmol) in 1 mL of DMF. After 10 minutes stirring methyliodide (2.47 μL, 0.04 mmol) was added. The resulting mixture was stirredat room temperature for 18 h. After evaporation the crude compound waspurified by chromatography on silica. Elution with toluene/ethyl acetate7:3 gavetrans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoro-N-methylacetamide(14 mg, 90%). Data: (m/z)=411 (M+H)⁺.

Example 29trans-N-(7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetimidamide(Structure 15 of Scheme II, where R1=H, R2=H, R3=Cl, R4=H, R5=H,R15=CF₃, X=O

Trifluoroacetonitrile was added to a solution oftrans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(10 mg, 0.03 mmol) in 2 mL of THF for 2 h. The mixture was stirred atroom temperature for 16 hr. After evaporation the crude compound waschromatographed on silica. Elution with toluene gavetrans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetimidamide(7.14 mg, 55%). Data: (m/z)=396 (M+H)⁺.

Example 30Trans-(7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicAcid Chloromethyl Ester (Structure 16 of Scheme III, where R1=R2=H,R3=Cl, R4=R5=H, R16=CH₂Cl, X=O)

General Method 15: N-acylation of an Amine of Structure 11 to aCarbamate of Structure 16.

100 μL of saturated aq. sodium bicarbonate was added totrans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(9.5 mg, 0.03 mmol) and chloromethyl chloroformate (64.2 μL, 0.42 mmol)in 250 μL of CH₂Cl₂. The resulting mixture was stirred at roomtemperature for 18 h. Subsequently, ethyl acetate was added and theorganic layer was washed with water, dried (Na₂SO₄) and evaporated togivetrans-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicacid chloromethyl ester (9.9 mg, 88%). Data: (m/z)=393 (M+H)⁺.

Example 31trans-(7-Chloro,2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicAcid 2-bromoethyl Ester (Structure 16 of Scheme III, where R1=R2=H,R3=Cl, R4=R5=H, R16=CH₂CH₂Br, X=O)

This compound was prepared by General Method 15 to affordtrans-(7-chloro,2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicacid 2-bromoethyl ester (yield 80%). Data: (m/z)=452 (M+H)⁺.

Example 32trans-N-(7-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-N′-(2-methylpropyl)thiourea(Structure 17 of Scheme III, where R1=R2=H, R3=Cl, R4=R5=H,R17=CH₂CH(Me)₂, X=O)

General Method 16: Isobutyl isothiocyanate (3.35 mg, 0.03 mmol) wasadded totrans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(5 mg, 0.02 mmol) in 1 mL of THF. The resulting mixture was stirred atroom temperature for 18 h. The mixture was evaporated under reducedpressure. Crystallisation from methanol gavetrans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-N′-(2-methylpropyl)thiourea(1 mg, 12%). Data: (m/z)=416 (M+H)⁺.

The following thioureas listed in Table 3 were prepared essentially byGeneral Method 16, using the appropriate starting materials. They arereferred to as examples 33 through 35. TABLE 3 Ex R1 R2 R3 R4 R5 R6 R7 XR17 (m/z) Yield(%) 33 H H Cl H H C(S)NR17 H O cC₆H₁₁ 442 20 34 H H Cl HH C(S)NR17 H O CH₂CH═CH₂ 400 26 35 H H Cl H H C(S)NR17 H O C(Me)₃ 416 12

Example 36trans-N-(2-Methylpropyl)-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(Structure 18 of Scheme III, where R1=R2=H, R3=Cl, R4=R5=H,R18=CH(CH₃)₂, X=O)

General Method 17: N-alkylation of an Amine of Structure 11 to anN-alkyl of Structure 18.

After 10 min. stirring sodium triacetoxyborohydride (11 mg, 0.05 mmol)was added totrans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(10 mg, 0.03 mmol) and isobutyraldehyde (3.45 mg, 0.03 mmol) in 1 mL ofCH₂Cl₂ (pH=4). The resulting mixture was stirred at room temperature for18 h. The mixture was evaporated and chromatographed on silica. Elutionwith CH₂Cl₂/methanol 8:2 gavetrans-N-(2-methylpropyl)-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(13 mg, 100%). Data: (m/z)=357 (M+H)⁺.

Example 37trans-N-Propyl-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(Structure 18 of Scheme III, where R1=R2=H, R3=Cl, R4=R5=H, R18=CH₂CH₃,X=O)

This compound was prepared by General Method 17 to affordtrans-N-propyl-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(10 mg, 97%). Data: (m/z)=343 (M+H)⁺.

Examples 38A and Btrans-N-(7,8-Dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Example 38A) (Structure 19A of Scheme IV, where R1=H, R4=R5=H, R15=CF₃,X=O)trans-N-(6,7-Dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Example 38B) (Structure 19B of Scheme IV, where R1=R2=H, R5=H, R15=CF₃,X=O)

N-chlorosuccinimide (6.87 mg, 0.05 mmol) and 0.5 μL 1N HCl was added totrans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(20 mg, 0.05 mmol) in 102 μL of acetone. The resulting mixture wasstirred at room temperature for 18 h. No reaction was observed. Thereaction was repeated under the same conditions. The resulting mixturewas stirred at room temperature for 1.5 h. The organic layer was washedwith saturated aq. sodium bicarbonate and water, dried (Na₂SO₄) andevaporated and the crude compound was purified by preparative HPLC togivetrans-N-(6,7-dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(3.6 mg, 17%) andtrans-N-(7,8-dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(1.6 mg, 7%). Data: (m/z)=431 (M+H)⁺.

Example 39trans-N-(8-Bromo-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 20 of Scheme IV, where R1=H, R4=H, R5=H, R15=CF₃, X=O)

N-bromosuccinimide (9.2 mg, 0.05 mmol) and 0.5 μL of 1N HCl were addedtotrans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(20 mg, 0.05 mmol) in 512 μL of acetone. The resulting mixture wasstirred at room temperature for 30 min. The mixture was diluted withethyl acetate, washed with saturated aq. sodium bicarbonate and water,dried (Na₂SO₄) and evaporated to givetrans-N-(8-bromo-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamideas a white solid (31 mg, 100%). Data: ¹H-NMR (400 MHz, CDCl₃) 1.85 (m,4H), 2.27 (m, 2H), 3.20 (m, 1H), 3.64 (m, 1H), 4.44 (d, J=8.0, 1H), 4.65(m, 1H), 6.26 (b, 1H), 7.02 (s, 1H), 7.10 (dt, J=8.0, 2.0, 1H), 7.16 (m,2H), 7.30 (dt, J=8.0, 3.0, 1H), 7.35 (s, 1H). (m/z)=477 (M+H)⁺.

Example 40trans-N-(2,3,4,14b-Tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 21 of Scheme IV, where R1=R2=R4=R5=H, R15=CF₃, X=O)

10 mg Pd/C 10% was added to a solution oftrans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(100 mg, 0.25 mmol) in 5 mL of DMF. The suspension was shaken under H₂atmosphere for 2 days. The mixture was filtered, poured into water andextracted with diethyl ether. The organic layer was washed with water,dried (Na₂SO₄) and evaporated to givetrans-N-(2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(89 mg, 98%). Data: ¹H-NMR (400 MHz, CDCl₃) 1.85 (m, 3H), 2.99 (m, 1H),3.18 (m, 1H), 3.75 (m, 1H), 4.50 (d, J=8,1H), 4.72 (m, 1H), 6.62 (br,1H), 6.84-7.30 (8 arH). (m/z)=362 (M+H)⁺.

Example 41trans-N-(7-Chloro-8-nitro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 22 of Scheme IV, where R1=H, R4=H, R5=H, R15=CF₃, X=O)

Nitric acid (50 μL, 1.10 mmol) was added at 0° C. to a suspension oftrans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(210 mg, 0.53 mmol) in 4 mL of CH₂Cl₂. After stirring the mixture wasextracted with ethyl acetate and the organic layer was washed with 5%aq. sodium bicarbonate, dried (Na₂SO₄) and evaporated to givetrans-N-(7-chloro-8-nitro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(219 mg, 90%). Data: ¹H-NMR (400 MHz, DMSO) 1.64-1.94 (m, 3H), 2.05 (br,1H), 3.26 (t, J=8.0, 1H), 4.20 (d, J=8.0, 1H), 4.35 (d, J=8.0, 1H), 4.60(dq, J=8.0, 3.0, 1H) 7.15 (m, 1H), 7.11-9.21 (6 ArH). (m/z)=443 (M+H)⁺.

Examples 42A and Btrans-N-(6-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Example 42A) (Structure 23A of Scheme V, where R1=H, R4=R5=H, R15=CF₃,X=O)trans-N-(8-Chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Example 42B) (Structure 23B of Scheme V, where R1=R2=R5=H, R15=CF₃,X=O)

N-chlorosuccinimide (8.52 mg, 0.06 mmol) and 0.67 μL of 1N HCl wereadded totrans-N-(2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(21 mg, 0.06 mmol) in 1 mL of acetone. The resulting mixture was stirredat room temperature for 2 h. The mixture was poured into water andextracted with ethyl acetate. The organic layer was washed withsaturated aq. sodium bicarbonate and evaporated. The crude compound waschromatographed on silica. Elution with heptane/ethyl acetate 8:2 gavethe two compounds, one of which wastrans-N-(6-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(9.8 mg, 41%). Data: ¹H-NMR (400 MHz, CDCl₃) 1.84 (m, 3H), 2.22 (m, 1H),3.17 (m, 1H), 3.52 (m, 1H), 4.44 (d, J=8.0, 1H), 4.69 (m, 1H), 6.48 (br,1H), 6.90 (d, J=8.0, 1H), 6.97 (dd, J=8.0, 3.0, 1H), 7.10 (dt, J=8.0,2.0, 1H), 7.13 (d, J=3.0, 1H), 7.19 (d, J=8.0, 2H), 7.29 (dt, J=8.0,2.0, 1H). (m/z)=397 (M+H)⁺.

The 8-chloro substituted compound containing 6,8-dichloro-substitutedcompound was purified by preparative HPLC to givetrans-N-(8-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(1.2 mg, 5%). Data: ¹H-NMR (400 MHz, CDCl₃) 1.84 (m, 3H), 2.00 (m, 1H),2.93 (dd, J=8.0, 3.0, 1H), 3.28 (dt, J=8.0, 3.0, 1H), 4.39 (s, 1H), 4.89(m, 1H), 7.07-7.33 (7 arH), 8.07 (br, 1H). (m/z)=397 (M+H)⁺.

Example 43trans-N-(7-Chloro-2,3,4,14b-tetrahydro-8-[bis(phenylsulfonyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 25 of Scheme VI, where R1=H, R4=H, R5=H, R11=R12=S(O)₂Ph,R15=CF₃, X=O)trans-N-(8-Amino-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide

80 μL 36% HCl and SnCl₂.2H₂O (600 mg, 2.66 mmol) were addedtrans-N-(7-chloro-8-nitro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(215 mg, 0.49 mmol) in 10 mL of ethanol. The resulting mixture wasstirred at 60° C. for 18 h. After cooling the mixture was evaporated anddissolved in ethyl acetate. Aq. sodium bicarbonate was added to thesolution (Sn salts were formed) followed by decalite and the mixture wasfiltered. The filtrate was extracted with ethyl acetate and the organiclayer was washed with brine, dried (Na₂SO₄) and evaporated to give thetitle compound (194 mg, 82%). Data: (m/z)=413 (M+H)⁺.

trans-2,2,2-Trifluoro-N-(7-chloro-2,3,4,14b-tetrahydro-8-[bis(phenylsulfonyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)acetamide(Structure 25 of Scheme VI, where R1=H, R4=H, R5=H, R11=R12=S(O)₂Ph,R15=CF₃, X=O)

General Method 18: N-acylation of an amine of Structure 25 to an amideof Structure 26 Benzenesulfonyl chloride (5 μL, 0.04 mmol) was addedunder N₂ totrans-N-(8-amino-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2,-trifluoroacetamide(5.0 mg, 0.01 mmol) in a mixture of 1 mL of CH₂Cl₂ and 25 μL oftriethylamine. The resulting mixture was stirred at 40° C. for 4 h.After cooling the mixture was evaporated and the crude compound waspurified by chromatography on silica. Elution with toluene/ethyl acetate1:0→0:1 (gradient) gavetrans-N-(7-chloro-2,3,4,14b-tetrahydro-8-[bis(phenylsulfonyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(7.3 mg, 83%). Data: (m/z)=692 (M+H)⁺.

Example 44trans-N-(7-Chloro-2,3,4,14b-tetrahydro-8-[bis(methylsulfonyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 25 of Scheme VI, where R1=H, R4=H, R5=H, R11=R12=S(O)₂CH₃,R15=CF₃, X=O)

This compound was prepared by General Method 18 using the appropriatestarting material to affordtrans-N-(7-chloro-2,3,4,14b-tetrahydro-8-[bis(methylsulfonyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(6.8 mg, 92%). Data: (m/z)=568 (M+H)⁺.

Example 45trans-N-(7-Chloro-2,3,4,14b-tetrahydro-8-[(phenylsulfonyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 25 of Scheme VI, where R1=H, R4=H, R5=H, R11=H, R12=S(O)₂Ph,R15=CF₃, X=O)

Benzenesulfonyl chloride (10 μL, 0.08 mmol) was added under N₂ totrans-N-(8-amino-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(5.0 mg, 0.01 mmol) in 1 mL of CH₂Cl₂ and 2 μL (1.1 eq) oftriethylamine. The resulting mixture was stirred at 35° C. for 4 h.After cooling the mixture was evaporated and the crude compound waspurified by chromatography on silica. Elution with toluene/ethyl acetate1:0→0:1 (gradient) gavetrans-N-(7-chloro-2,3,4,14b-tetrahydro-8-[(phenylsulfonyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(2.4 mg, 32%). Data: (m/z)=552 (M+H)⁺.

Example 46trans-N-(7-Chloro-2,3,4,14b-tetrahydro-1-(2,2,2-trifluoroacetylamino)1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-8-yl)carbamicAcid 1,1-dimethylethyl Ester (Structure 25 of Scheme VI, where R1=H,R4=H, R5=H, R11=H, R12=C(O)OC(CH₃)₃, R15=CF₃, X=O)

Di-tert-butyl dicarbonate (20.55 mg, 0.09 mmol) was added at 5° C. underN₂ totrans-N-(8-amino-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(10.8 mg, 0.03 mmol) in 1 mL of THF and 6 μL (1.1 eq) of triethylamine.The resulting mixture was stirred at 50° C. for 72 h. After cooling themixture was evaporated and chromatographed on silica. Elution withheptane/ethyl acetate 1:0→0:1 (gradient) gave the title compound (2.7mg, 15%). Data: (m/z)=512 (M+H)⁺.

Example 47trans-N-(6,7-Dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)acetamide(Structure 19B of scheme IV, where X=O, R1=H, R2=H, R5=H, R15=CH₃)

To a solution oftrans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]-pyrido[1,2-d][1,4]oxazepin1-yl)acetamide(Structure 12 of Scheme II, where R1=H, R2=H, R3=Cl, R4=R5=H, R15=CH₃,X=O) (0.63 g, 1.84 mmol) in acetone (15 mL) were addedN-chlorosuccinimide (246 mg, 1.84 mmol) and 6N (aq) HCl (3.1 mL). Theresulting suspension was stirred at room temperature for 20 h. A secondamount of N-chlorosuccinimide (246 mg, 1.84 mmol) was added andsubsequently the reaction mixture was stirred at room temperature for 4h. The reaction mixture was extracted with ethyl acetate (3×), washedwith sat. (aq) NaHCO₃ (3×), 10% (aq) NaCl (2×) and dried (Na₂SO₄). Thesolvents were removed under reduced pressure. The solid was purified bycolumn chromatography (silicagel, toluene/ethanol=9/1). Subsequentpurification by HPLC resulted in the title compound (137 mg, 36.4%).Data: ¹H-NMR (400 MHz, CDCl₃) 1.55 (m, 1H), 1.82 (m, 2H), 1.94-2.20 (m,1H), 2.10 (s, 3H), 2.92 (m, 1H), 3.11 (td, J=12.6, 4.2, 1H), 4.39 (d,J=1.9, 1H), 4.86 (m, 1H), 7.02-7.36 (m, 6 ArH).

Example 48trans-7-Chloro-2,3,4,14b-tetrahydro-N-(2-methoxyethyl)-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(Structure 26 of Scheme III, where R1=H, R2=H, R3=Cl, R4=H, R5=H)

To a solution oftrans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(84 mg, 0.28 mmol) in DMF (400 μl) were added 2-methoxyethyl bromide (37μl, 0.39 mmol) and triethylamine (47 μl, 0.36 mmol). The resultingreaction mixture was stirred at 60° C. for 18 h. After cooling down,ethyl acetate was added. The mixture was washed with sat. (aq) NaHCO₃and water. The organic layer was dried and evaporated. The crudecompound was purified with HPLC and freeze-dried to afford the titlecompound (32 mg, 32%). Data (m/z)=359 (M+H)⁺.

Example 49 1,1-Dimetylethyltrans-2-[(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]thiazepin-1-yl)amino]acetate(Structure 27 of Scheme III, where R1=H, R2=H, R3=Cl, R4=H, R5=H)

To a solution of the HBr salt oftrans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]thiazepine-1-amine(200 mg, 0.5 mmol) in DMF (10 mL) was added DIPEA (219 μl, 1.3 mmol) andt-butyl bromoacetate (89 μl, 0.6 mmol). The reaction mixture was stirredat room temperature for 5.5 h. After pouring the reaction mixture intowater it was extracted with ethyl acetate (3×). The combined organiclayers were washed with brine, dried (Na₂SO₄) and evaporated. The crudeproduct was purified on silica with heptane/ethyl acetate 8:2 to givethe pure product (90 mg, 41%). Data: (m/z)=431 (M+H)⁺.

Example 50trans-N-(6,7-Dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)formamide(Structure 29 of scheme VII)trans-6,7-Dichloro-2,3,4,14b-tetrahydro-N-(2-methoxyethyl)-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(Structure 28 of Scheme VII)

K₂CO₃ (537 mg, 3.9 mmol) was added to a solution oftrans-N-(6,7-dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(322 mg, 0.75 mmol) in methanol (28 mL) and water (1.7 mL). The reactionmixture was stirred at reflux temperature for 2 h whereafter themethanol was removed under reduced pressure. Water was added to theremaining product and the water layer was extracted with CH₂Cl₂ (3×).The combined organic layers were washed with brine, dried (Na₂SO₄) andevaporated to give the crude title compound (266 mg, 100%).

trans-N-(6,7-Dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)formamide(Structure 29 of scheme VII)

A solution oftrans-6,7-dichloro-2,3,4,14b-tetrahydro-N-(2-methoxyethyl)-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(122 mg, 0.36 mmol) in ethyl formate was stirred overnight at refluxtemperature. After removal of the solvent under reduced pressure, theremaining product was purified with preparative LC-MS to give the titlecompound (40 mg, 30%). Data (m/z)=397 (M+H)⁺.

Example 51trans-N-(6-Bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 36 of Scheme IX where X=O, R1=H, R2=H, R3=H, R4=Br, R5=H,R10=H) 2-[(2,6-Dibromophenyl)iminomethyl]phenol (Structure 30 of SchemeVIII where R2=H)

General Method 19: Formation of an Imine of Structure 30 Out of an Amineand an Aldehyde.

A solution of 2,6-dibromoaniline (9 g, 35.9 mmol), salicylaldehyde (2.79mL, 35.9 mmol) and p-toluenesulfonic acid (20 mg, 0.1 mmol) in toluene(180 mL) was heated to reflux in a Dean-Stark apparatus for 2 h. Afteradding some triethylamine the reaction mixture was evaporated resultingin crude compound 2-[(2,6-dibromophenyl)iminomethyl]phenol (14 g, 100%).

9-Bromodibenzo[b,f][1,4]oxazepine (Structure 31 of Scheme VIII whereX=O, R1=H, R2=H, R3=H, R4=Br, R5=H, R10=H)

General Method 20: Ring Closure by Etherification to Structure 31.

To a solution of 2-[(2,6-dibromophenyl)iminomethyl]phenol (14.1 g, 35.9mmol) in 350 mL of DMSO, K₂CO₃ (9.9 g, 71.8 mmol) and 18-Crown-6 (95 mg,0.36 mmol) were added. The resulting mixture was stirred at 140° C. for1.5 h and was then allowed to cool to ambient temperature overnight. Themixture was poured into ice-water and extracted with ethyl acetate (3×).The organic solution was washed with water and brine, and subsequentlydried (MgSO₄). Removal of the solvent in vacuo resulted in crude9-bromodibenzo[b,f][1,4]oxazepine (9.79 g 99%). Data: (m/z)=274+276(M+H)⁺.

trans-6-Bromo-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylicAcid (Structure 32 of Scheme IX where X=O, R1=H, R2=H, R3=H, R4=Br,R5=H, R10=H)

General Method 21: Addition of Glutaric Anhydride to a Cyclic Amine,Resulting in the Formation of a Tetracycle of Structure 32.

Glutaric anhydride (5.22 g, 45.8 mmol) was added to a stirred solutionof 9-bromo-dibenzo[b,f][1,4]oxazepine (9.29 g, 33.9 mmol) in xylene (9mL). The mixture was heated to 140° C. for 72 h. Equal parts of etherand of ethyl acetate were added whereafter the product was collected byfiltration. The crystals were dried at 50° C. under reduced pressure toyield the title compound as one isomer (5.5 g, 39%, trans). The eluentwas extracted with 2N NaOH (aq.). By adding 3N HCl (aq.) to the aqueouslayer the pH was adjusted to pH 2. The aqueous layer was extracted withethyl acetate, washed with brine and dried. After removal of ethylacetate under reduced pressure a mixture of isomers was obtained (6.1 g,47%). Data: (m/z)=388+390 (M+H)⁺.

(trans-6-Bromo-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicAcid 1-ethylpropyl Ester (Structure 33 of Scheme IX where X=O, R1=H,R2=H, R3=H, R4=Br, R5=H, R10=H, R22=CH(C₂H₅)₂

General Method 22: Curtius Rearrangement and Subsequent Formation of aCarbamate of Structure 33.

To a solution oftrans-6-bromo-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylicacid (5.1 g, 13.1 mmol) in toluene (185 mL), triethylamine (3.3 mL, 23.6mmol) and DPPA (3.67 mL, 17.0 mmol) were added. The reaction mixture washeated to reflux for 1 h. Subsequently, 3-pentanol (2.8 mL, 26.2 mmol)was added and stirring was continued for 1.5 h at 110° C. After coolingdown the reaction mixture was poured into ice-water, extracted withethyl acetate, washed with water and brine, dried (MgSO₄) andevaporated, which resulted in the crude title compound (7.4 g, 100%).Data: (m/z)=473+475 (M+H)⁺.

(trans-6-Bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicAcid 1-ethylpropyl Ester (Structure 34 of Scheme IX where X=O, R1=H,R2=H, R3=H, R4=Br, R5=H, R10=H, and R22=CH(C₂H₅)₂)

General Method 23: Formation of Structure 34 by Borane Reduction of anAmide Functionality.

Borane (1.0 M in THF, 60 mL, 60 mmol) was added dropwise to a stirredsolution oftrans-(6-bromo-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicacid 1-ethylpropyl ester (7.4 g, 13.1 mmol) in THF (90 mL). Theresulting mixture was stirred at ambient temperature for 1 h.Subsequently, hydrochloric acid (1N aq) was added dropwise untilevolution of gas ceased. A solution of sodium hydroxide (2N aq) wasadded to the mixture to adjust the pH to 8. The resulting reactionmixture was extracted with ethyl acetate, and the extract wassubsequently washed with water and brine. After drying (MgSO₄) thesolvent was evaporated under reduced pressure to yield the crude titlecompound (7 g, 100%). Data: (m/z)=459+461 (M+H)⁺.

trans-6-Bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-ylamine(Structure 35 of Scheme IX, where X=O, R1=H, R2=H, R3=H, R4=Br, R5=H,R10=H)

General Method 24: Hydrolysis of an Amide Functionality, Resulting in anAmine of Structure 35.

A mixture of acetic acid (100 mL) and hydrogen bromide (48%, 50 mL) wasadded totrans-(6-bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]-oxazepin-1-yl)carbamicacid 1-ethylpropyl ester and stirred for 1 h at 100° C. After coolingdown the reaction mixture was poured into a cold 1N NaOH (aq) solution.It was extracted with ethyl acetate and the organic layer was washedwith 1N NaOH (aq) 4×, sat. NaHCO₃ (aq), dried (MgSO₄) and the solventwas evaporated. The crude compound was purified on silica withtoluene/acetone 9:1 to yield the title compound (2.4 g, 53%). Data:(m/z)=345+347 (M+H)⁺.

trans-N-(6-Bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 36 of Scheme IX, where X=O, R1=H, R2=H, R3=H, R4=Br, R5=H,R10=H)

General Method 25: Addition of Trifluoroacetic Anhydride to an AmineYielding a Trifluoroacetamide of Structure 36.

To a solution oftrans-6-bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-ylamine(2.4 g, 6.95 mmol) in a mixture of CH₂Cl₂ (10 mL) and pyridine (10 mL),trifluoroacetic anhydride (5 mL, 35.4 mmol) was added. The resultingreaction mixture was stirred at ambient temperature for 0.5 h.Subsequently, water was added under cooling in an ice bath. The mixturewas extracted with CH₂Cl₂ (2×). The combined organic layers were washedwith brine, dried (MgSO₄), evaporated and stripped with toluene (2×) togive the title compound (1.54 g, 50%). Data: ¹H-NMR (400 MHz, DMSO)1.59-2.05 (m, 4H), 3.09-3.17 (m, 1H), 3.87 (d, J=14.0, 1H), 4.14 (d,J=10, 1H), 4.40-4.49 (m, 1H), 6.70-7.28 (m, 7 ArH), 9.13 (d, J=10, 1NH).(m/z)=441+443 (M+H)⁺.

Example 52trans-N-(6-Acetyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 37 of Scheme X, where R2=H)

General Method 26: Conversion of Bromide into an Acetyl of Structure 37.

(1-Ethoxyvinyl)-tributyl tin (182 μl, 0.54 mmol) was added to a solutionoftrans-N-(6-bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(200 mg, 0.45 mmol) and PdCl₂(PPh₃)₂ (6 mg, 9 μmol) in toluene (12 mL)under N₂. The reaction mixture was heated to reflux and stirred for 3 h.3 N (aq) HCl was added slowly at room temperature and the reacionmixture was stirred for a further ten minutes. It was then poured intowater and extracted with ethyl acetate. The organic layer was washedwith sat. NaHCO₃ (aq) and brine, dried (MgSO₄) and the solvents wereevaporated. The crude product was purified, dissolved in THF (10 mL) andsubsequently 3N HCl (aq) (4 mL) was added. The mixture was stirred atroom temperature for 1 h, poured into water and extracted with ethylacetate. The organic layer was washed with sat. NaHCO₃ and brine, driedand evaporated. After purification on HPLC the title compound wasobtained (49 mg, 27%). Data: ¹NMR (400 MHz, CDCl₃) 1.50 (m, 1H),1.65-1.75 (m, 1H), 1.79-1.93 (m, 2H), 2.50 (d, J=3, 3H), 2.82 (m, 1H),3.38 (dt, J=12, 4, 1H), 4.5 (d, J=3, 1H), 4.83 (m, 1H), 7.09-7.34 (7ArH).

Example 53trans-2,3,4,14b-Tetrahydro-1-[(trifluoroacetyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-6-carbonitrile(Structure 38 of Scheme X, where R2=H)

General Method 27: Conversion of a Bromide into a Cyano Derivative ofStructure 38.

Copper(I) cyanide (142 mg, 1.6 mmol) was added to a solution oftrans-N-(6-bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(700 mg, 1.6 mmol) in 1-methyl-2-pyrrolidinone (28 mL) and heated to200° C. and stirred for 24 h at 190° C. Water was added at roomtemperature and the mixture was extracted with ethyl acetate. Theorganic layer was washed with brine, dried (MgSO₄) and concentratedunder reduced pressure. Purification on silica with heptane/ethylacetate 1:1 gave the title compound (450 mg, 75%). Data: ¹NMR (400 MHz,CDCl₃) 1.69-1.75 (m, 1H), 1.87-1.93 (m, 1H), 2.01-2.16 (m, 2H),3.14-3.29 (m, 2H), 4.61 (d, J=3.2, 1H), 4.91 (m, 1H), 7.11-7.37 (7 ArH).

Example 54trans-N-(6-Ethenyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 39 of Scheme X, where R2=H)

General Method 28: Conversion of a Bromide into a Vinyl Derivative ofStructure 39.

To a solution oftrans-N-(6-bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido-[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(50 mg, 0.11 mmol) in toluene (3 mL) was added PdCl₂(PPh₃)₂ andvinyltributyl tin (38 μl, 0.13 mmol). The resulting reaction mixture washeated to 110° C. and stirred for 2 h at 110° C. After cooling to roomtemperature, water was added and the mixture was extracted with ethylacetate. The organic layer was washed with water and brine, dried(MgSO₄) and the solvent was evaporated. After purification by HPLC thetitle compound was obtained (23 mg, 52%). Data: ¹NMR (400 MHz, CDCl₃)1.60 (m, 1H), 1.78 (m, 1H), 1.83-1.96 (m, 2H), 2.93 (m, 1H), 3.43 (dt,J=12, 4, 1H), 4.35 (d, J=2.5, 1H), 4.84 (m, 1H), 5.40 (d, J=11, 1H),5.67 (dd, J=18, 1.8, 1H), 7.07-7.31 (7 ArH), 7.55 (NH, 1H).

Example 55trans-N-(2,3,4,14b-Tetrahydro-6-methoxy-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 41 of Scheme X, where R2=H)

Copper(I) iodide (21 mg, 0.11 mmol) was added to a stirring solution oftrans-N-(6-bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(100 mg, 0.22 mmol) in DMF (1.5 mL) in a Dean-Stark apparatus.Subsequently a solution of NaOMe (1.2 mL, 1.2 mmol) in methanol wasadded and stirring was continued at 135° C. for 4 h. After cooling down,the reaction mixture was poured into sat (aq) NH₄Cl and extracted withethyl acetate. The organic layer was washed with brine, dried (MgSO₄)and evaporated. After purification on a SPE-column and by HPLC the titlecompound (11 mg, 13%) was obtained. Data: ¹H-NMR (400 MHz, CDCl₃) 1.50(m, 1H), 1.76 (m, 1H), 1.87 (m, 1H), 1.94 (m, 1H), 2.87 (m, 1H), 3.29(dt, J=12, 3.2, 1H), 3.86 (s, 3H), 4.28 (d, J=3.2, 1H), 4.81 (m, 1H),(Ar) 6.66 (d, J=12, 1H), 6.78 (d, J=12, 1H), 7.10 (m, 1H), 7.20-7.31 (m,4H), 8.18 (m, 1H, NH).

Example 56trans-N-(6-Bromo-8-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 36 of Scheme IX where X=O, R1=H, R2=F, R3=H, R4=Br, R5=H,R10=H) 2-[(2,6-Dibromo-4-fluorophenyl)iminomethyl]phenol (Structure 30of Scheme VIII where R2=F)

This compound was prepared by general method 19 to afford the crudetitle compound (15.2 g, 100%). Data: (m/z)=372+374+376 (M+H)⁺.

9-bromo-7-fluorodibenzo[b,f][1,4]oxazepine (Structure 31 of Scheme VIIIwhere X=O, R1=H, R2=F, R3=H, R4=Br, R5=H, R10=H)

This compound was prepared by general method 20.9-Bromo-7-fluorodibenzo[b,f][1,4]oxazepine (6.7 g, 64%) was collected byfiltration after pouring the reaction mixture into ice-water. Data:(m/z)=292+294 (M+H)⁺.

trans-6-Bromo-8-fluoro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylicAcid (Structure 32 of Scheme IX where X=O, R1=H, R2=F, R3=H, R4=Br,R5=H, R10=H)

This compound was prepared by general method 21 to afford the titlecompound as crystals of only one isomer (4.2 g, 45%). Data:(m/z)=406+408 (M+H)⁺.

(trans-6-Bromo-8-fluoro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicAcid 1-ethylpropyl Ester (Structure 33 of Scheme IX where X=O, R1=H,R2=F, R3=H, R4=Br, R5=H, R10=H) This compound was prepared by generalmethod 22 to afford the title compound (4.6 g, 100%). Data:(m/z)=435+437 (M+H)⁺.

(trans-6-Bromo-8-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicAcid 1-ethylpropyl Ester (Structure 34 of Scheme IX where X=O, R1=H,R2=F, R3=H, R4=Br, R5=H, R10=H)

This compound was prepared by general method 23. The product (1.2 g,30%) was obtained by crystallisation from diethyl ether. Data:(m/z)=421+423 (M+H)⁺.

trans-6-Bromo-8-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(Structure 35 of Scheme IX, where X=O, R1=H, R2=F, R3=H, R4=Br, R5=H,R10=H)

This compound was prepared by general method 24 to afford the pure titlecompound (2.1 g, 72%) after purification on a SPE column. Data:(m/z)=363+365 (M+H)⁺.

trans-N-(6-Bromo-8-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 36 of Scheme IX, where X=O, R1=H, R2=F, R3=H, R4=Br, R5=H,R10=H)

This compound was prepared by general method 25 to afford the titlecompound. After purification with HPLC 79 mg (91%) was obtained. Data:¹H-NMR (400 MHz, CDCl₃) 1.54-1.61 (m, 1H), 1.67-1.77 (m, 1H), 1.82-1.90(m, 1H), 1.93-2.06 (m, 1H), 2.85-2.92 (dd, J=12.2, J=5.0, 1H), 3.27-3.35(td, J=12.0, J=3.0, 1H), 4.33-4.35 (d, J=2.2, 1H), 4.87-4.92 (m, 1H),6.88-7.34 (6 ArH), (br, 1H). (m/z)=459+461 (M+H)⁺.

Example 57trans-N-(6-Acetyl-8-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 37 of Scheme X, where R2=F)

This compound was prepared by general method 26 to afford the titlecompound (103 mg, 42.9%) after purification by HPLC. Data: ¹H-NMR (400MHz, CDCl₃) 1.46-1.69 (m, 2H), 1.76-1.93 (m, 2H), 2.58 (s, 3H),2.76-2.82 (m, 1H), 3.34-3.43 (td, J=12.0, 3.2, 1H), 4.44-4.47 (d, J=2.2,1H), 4.80-4.86 (m, 1H), 6.99-7.32 (6 ArH), 8.5-8.58 (br, 1H). (m/z)=423(M+H)⁺.

Example 58trans-8-Fluoro-2,3,4,14b-tetrahydro-1-[(trifluoroacetyl)amino]-1H-dibenzo[b,f]pyrido-[1,2-d][1,4]oxazepine-6-carbonitrile(Structure 38 of Scheme X, where R2=F)

This compound was prepared by general method 27. After purification byHPLC the title compound (78 mg, 55.7%, trans) was obtained. Data: ¹H-NMR(400 MHz, CDCl₃) 1.65-1.72 (m, 1H), 1.85-1.92 (m, 1H), 1.95-2.02 (m,1H), 2.05-2.14 (m, 1H), 3.06-3.11 (m, 1H), 3.17-3.23 (td, J=8.0, J=2.0,1H), 4.55-4.57 (d, J=1.7, 1H), 4.90-4.94 (m, 1H), 7.06-7.36 (6 ArH),7.47-7.56 (br, 1H). (m/z)=406 (M+H)⁺.

Example 59trans-N-(6-Ethenyl-8-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]-oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 39 of scheme X, where R2=F)

This compound was prepared by general method 28 to afford the titlecompound (141 mg, 53%) after purification on HPLC. Data: ¹H-NMR (400MHz, CDCl₃) 1.57-1.77 (m, 2H), 1.82-1.95 (m, 2H), 2.86-2.92 (m, 1H),3.40-3.48 (td, J=12.0, J=3.0, 1H), 4.27-4.30 (d, J=2.5, 1H), 4.82-4.87(m, 1H), 5.43-5.47 (d, J=11.4, 1H), 5.64-5.70 (dd, J=18.0, 1.1, 1H),6.81-7.32 (6 ArH+1H), 7.49-7.57 (br, 1H). (m/z)=407 (M+H)⁺.

Example 60trans-2,2,2-Trifluoro-N-(8-fluoro-2,3,4,14b-tetrahydro-6-methyl-1H-dibenzo[b,f]pyrido-[1,2-d][1,4]oxazepin-1-yl)acetamide(Structure 40 of Scheme X, where R2=F)

To a solution oftrans-N-(6-bromo-8-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(300 mg, 0.65 mmol) in THF (7 mL) was added ferrocene PdCl₂ (10 mg, 14mmol) and the reaction mixture was stirred for 10 min. Methylzincchloride (0.81 mL) was added dropwise whereafter the reaction mixturewas heated to 60° C. After 3 h ferrocene PdCl₂ (20 mg, 28 μmol) andmethylzinc chloride (0.3 mL) were added and the reaction mixture washeated at 80° C. for another hour. Water was added at room temperature,and the reaction mixture was extracted with ether and water. The ethersolution was washed with brine, dried (Na₂SO₄) and the volatiles wereremoved under reduced pressure. After purification by HPLC the titlecompound was obtained (108 mg, 39%). Data: ¹H-NMR (400 MHz, CDCl₃)1.56-1.72 (m, 2H), 1.79-1.93 (m, 2H), 2.37 (s, 3H), 2.79-2.86 (m, 1H),3.44-3.52 (td, J=12.0, J=3.0, 1H), 4.27-4.29 (d, J=2.5, 1H), 4.85-4.91(m, 1H), 6.70-7.32 (6 ArH), 7.63-7.70 (br, 1H). (m/z)=395 (M+H)⁺.

Example 61trans-N-(7-Bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 46 of Scheme XI) 4-Bromo-2-nitro-1-phenoxybenzene (Structure42 of Scheme XI)

Cs₂CO₃ (4 g, 12.3 mmol) was added to a solution of phenol (1 g, 10.6mmol) in 50 mL of THF under N₂ atmosphere. After stirring for 15 min.1,4-dibromo-2-nitrobenzene (2.81 g, 10 mmol) was added. The resultingmixture was heated to reflux and stirred overnight at reflux. Water andethyl acetate were added, followed by extraction with ethyl acetate(3×). The combined organic layers were washed with water and brine,dried (Na₂SO₄) and evaporated to give the crude compound (3.2 g, 75%).

5-Bromo-2-phenoxybenzeneamine (Structure 43 of Scheme XI)

Iron powder (3 g, 53.4 mmol) and acetic acid (10 mL) were added to astirred suspension of 4-bromo-2-nitro-1-phenoxybenzene (3.1 g, 9.5 mmol)in water (25 mL) of 60° C. The reaction mixture was heated to 80° C. andstirred for 30 min. After cooling to room temperature the reactionmixture was filtered and extracted with toluene. The toluene solutionwas washed with water (3×) and brine, dried (Na₂SO₄) and evaporated togive the crude compound (2.3 g, 87%). Data: (m/z)=264+266 (M+H)⁺.

N-(5-Bromo-2-phenoxyphenyl)formamide (Structure 44 of Scheme XI)

General Method 29: Addition of Formic Acid to an Amine YieldingFormamides of Structure 44.

A mixture of 5-bromo-2-phenoxybenzeneamine (68.4 g, 260 mmol) and formicacid (180 mL) was heated to reflux and stirred for 2 h. The product wascollected by filtration and dried at 50° C. under reduced pressure togive the compound as off-white crystals (60 g, 79%). Data: (m/z)=292+294(M+H)⁺.

8-Bromodibenzo[b,f][1,4]oxazepine (Structure 45 of Scheme XI)

General Method 30: Ring Closure with PPA Resulting in Derivatives ofStructure 45.

PPA (207.5 g) was added to N-(5-bromo-2-phenoxyphenyl)formamide (20 g,68.7 mmol) and the reaction mixture was heated to 140° C. with vigorousstirring for 2 h. After cooling to room temperature the reaction mixturewas poured into ice-water. The mixture was filtered and the solid waswashed with water and with 25% ammonia and dried at 50° C. under reducedpressure to yield the title compound (9.9 g, 52%). Data: (m/z)=274+276(M+H)⁺.

trans-7-Bromo-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylicAcid (Structure 32 of Scheme IX where X=O, R1=H, R2=H, R3=Br, R4=H,R5=H, R10=H)

Glutaric anhydride (5.48 g, 48.1 mmol) was added to a stirred solutionof 8-bromodibenzo[b,f][1,4]oxazepine (8.1 g, 29.6 mmol) in xylene (20mL). CH₂Cl₂ was added to the reaction mixture and this was extractedwith 2N (aq) NaOH (3×). All aqueous layers were neutralized by adding 2N(aq) HCl and extracted with CH₂Cl₂. The combined organic layers weredried (Na₂SO₄) and evaporated resulting in the title compound (9.7 g,85%) as a mixture of trans and cis. Data: (m/z)=388+390 (M+H)⁺.

trans-(7-Bromo-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicAcid 1-ethylpropyl Ester (Structure 33 of Scheme IX where X=O, R1=H,R2=H, R3=Br, R4=H, R5=H, R10=H, R22=CH(C₂H₅)₂)

By applying general method 22 and by using 3-pentanol as alcohol, thetitle compound was obtained (6.0 g, 99%). Data: (m/z)=470+472 (M+H)⁺.

trans-(7-Bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicAcid 1-ethylpropyl Ester (Structure 34 of Scheme IX where X=O, R1=H,R2=H, R3=Br, R4=H, R5=H, R10=H, R22=CH(C₂H₅)₂)

Borane (1.0 M in THF, 55 mL, 55 mmol) was added dropwise to a stirredsolution oftrans-(7-bromo-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicacid 1-ethylpropyl ester (6.01 g, 12.7 mmol) in THF (63 mL). Theresulting mixture was stirred at ambient temperature for 1 h.Subsequently, water was added and the resulting mixture was extractedwith ethyl acetate. The organic layers were washed with water and brine,dried (Na₂SO₄) and evaporated. The crude product was chromatographed onsilica with heptane/ethyl acetate 1:1 which gave the title product as amixture of cis and trans. After adding ethyl acetate to this mixture,pure trans product (1.41 g, 24.2%) could be collected throughfiltration. Data: (m/z)=459+461 (M+H)⁺.

trans-7-Bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(Structure 35 of Scheme IX where X=O, R1=H, R2=H, R3=Br, R4=H, R5=H,R10=H)

This compound was prepared by general method 24 to afford the titlecompound (1.05 g, 99%). Data: (m/z)=345+347 (M+H)⁺.

trans-N-(7-Bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 46 of Scheme XI)

This compound was prepared by general method 25 to afford the titlecompound (76 mg, 92%). Data: ¹H-NMR (400 MHz, DMSO) 1.58-2.09 (m, 4H),3.08 (t, J=12.8, 1H), 3.81 (d, J=14.0, 1H), 4.11 (d, J=10.4, 1H), 4.38(m, 1H), 6.83-7.28 (7 ArH), 9.13 (d, J=10.0, 1H), (m/z)=441+443 (M+H)⁺.

Example 62trans-N-(7-Acetyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 47 of Scheme XII)

(1-Ethoxyvinyl)tributyl tin (90 μl, 0.23 mmol) was added to a solutionoftrans-N-(7-bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(100 mg, 0.23 mmol) and PdCl₂(PPh₃)₂ (3 mg, 4.3 μmol) in toluene (6 mL)under N₂. The reaction mixture was heated to 140° C. and stirred for 3h. After cooling to room temperature, 2N (aq) HCl (450 ul) was added andthe reaction mixture was stirred for 1 h. The reaction was quenched withsat NaHCO₃ (aq) and extracted with ethyl acetate. The organic layer waswashed with brine, dried (Na₂SO₄) and evaporated. The crude compound waschromatographed with heptane/ethyl acetate 1:1. Purifcation by HPLC gavethe title compound (43 mg, 47%). Data: ¹H-NMR (400 MHz, DMSO) 1.60-2.09(m, 4H), 3.21 (t, J=11.2, 1H), 3.90 (d, J=14.0, 1H), 4.16 (d, J=10.4,1H), 4.44 (m, 1H), 7.04-7.54 (m, 10H), 9.20 (d, J=10.0, 1H). (m/z)=405(M+H)⁺.

Example 63trans-2,3,4,14b-Tetrahydro-1-[(trifluoroacetyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-7-carbonitrile(Structure 48 of Scheme XII)

This compound was generated by general method 27 to afford the titlecompound (491 mg, 50%). Data: ¹H-NMR (400 MHz, DMSO) 1.58-2.09 (m, 4H),3.16 (t, J=13.2, 1H), 3.96 (d, J=13.6, 1H), 4.18 (d, J=10.4, 1H), 4.47(m, 1H), 7.06-7.53 (m, 7 ArH), 9.18 (d, J=9.6, 1H). (m/z)=388 (M+H)⁺.

Example 64trans-N-(7-Ethenyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 49 of Scheme XII)

This compound was generated by general method 28 to afford the titlecompound (15 mg, 34%). Data: ¹H-NMR (400 MHz, DMSO) 1.59-2.07 (m, 4H),3.14 (t, J=12, 1H), 3.90 (d, J=13.6, 1H), 4.23 (d, J=10.0, 1H), 4.44 (m,1H), 5.15 (d, J=12.0, 1H) 5.50 (d, J=18.4, 1H) 6.60 (q, 1H) 6.84-7.26(m, 7 ArH), 9.17 (d, J=9.6, 1H). (m/z)=389 (M+H)⁺.

Example 65trans-2,2,2-trifluoro-N-[2,3,4,14b-tetrahydro-7-[(phenylmethyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl]acetamide(Structure 50 of Scheme XII)

To a solution oftrans-N-(7-bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]-oxazepin-1-yl)-2,2,2-trifluoroacetamide(0.5 g, 1.1 mmol) in DME (16 mL), Pd₂(dba)₃ (12.5 mg, 13.5 μmol),2-(di-t-butyl-phosphino)biphenyl (25 mg, 80 μmol), sodium-tert-butoxide(218 mg, 2.3 mmol) and benzylamine (243 mg, 2.3 mmol) were added. Theresulting reaction mixture was heated to 75° C. and stirred at thistemperature for 48 h. The reaction mixture was quenched with sat NaHCO₃(aq) and extracted with ethyl acetate. The organic layer was washed withwater and brine, dried (Na₂SO₄) and evaporated. The crude product waschromatographed with heptane/ethyl acetate 8:2 and purified with HPLC toafford the title compound (21 mg, 32%). Data: ¹H-NMR (400 MHz, DMSO)1.54-2.02 (m, 4H), 2.95 (t, J=9.2, 1H), 3.68 (d, J=14.0, 1H), 4.02 (d,J=10.0, 1H), 4.17 (d, J=6.0, 2H), 4.37 (m, 1H), 5.90-7.33 (12 ArH, 1NH), 9.11 (d, J=10.0, 1H). (m/z)=468 (M+H)⁺.

Example 66trans-N-(7-Amino-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 51 of Scheme XII)

To a solution oftrans-2,2,2-trifluoro-N-[2,3,4,14b-tetrahydro-7-[(phenylmethyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl]acetamide(944 mg, 2.0 mmol) in ethanol (16 mL) were added Pd/C 10% (111 mg) and asolution of 4M HCl in dioxane (778 μl, 3.11 mmol). The resultingreaction mixture was hydrogenated at 3 bar for 6 h. The reaction mixturewas quenched with sat. NaHCO₃ (aq) and diluted with ethanol. Afterfiltration through dicalite and thorough washing with ethyl acetate, thevolatiles were removed in vacuo. A part of the crude product waspurified with HPLC to afford the title compound (29 mg, 53%). Data(m/z)=378 (M+H)⁺.

Example 67trans-N-[2,3,4,14b-Tetrahydro-7-[(1-oxopropyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl]-2,2,2-trifluoroacetamide(Structure 52 of Scheme XII)

To a solution oftrans-N-(7-amino-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido-[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(50 mg, 0.13 mmol) in CH₂Cl₂ (2 mL) was added propionyl chloride (11 μl,0.13 mmol) and triethylamine (20 μl, 0.14 mmol). The reaction mixturewas stirred for 1.5 h at room temperature. The reaction mixture wasquenched with sat. NaHCO₃ (aq) and extracted with CH₂Cl₂. The organiclayer was dried and evaporated. The crude product was purified on silicaand by HPLC to afford the title compound (27 mg, 48%). Data (m/z)=434(M+H)⁺.

Example 68trans-N-(12-Bromo-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 55 of Scheme XIII)4-Bromo-2-[(4-bromo-2-fluorophenyl)methyleneamino]phenol (Structure 53of Scheme XIII)

5-Chloro-2-hydroxyaniline (9.8 g, 48 mmol) and4-bromo-2-fluorobenzaldehyde (7.0 g, 48 mmol) were dissolved in ethanol(400 mL). The reaction mixture was heated to 60° C. and stirred for 1 h.Subsequently the ethanol was evaporated and the title compound wasobtained (17.4 g, 100%).

3-Bromo-8-chlorodibenzo[b,f][1,4]oxazepine (Structure 54 of Scheme XIII)

To a solution of4-bromo-2-[(4-bromo-2-fluorophenyl)methyleneamino]phenol (17.4 g, 48.5mmol) in DMSO (200 mL) was added K₂CO₃ (13.4 g, 97.1 mmol). Theresulting reaction mixture was stirred at 140° C. for 1 h. Water wasadded at 45° C. The product was collected by filtration as an off-whitesolid. The solid was washed with water, dissolved in ethyl acetate andwashed with sat. (aq) NaCl and dried (Na₂SO₄). The volatiles wereevaporated to give the title compound (14.3 g, 95.5%).

trans-12-Bromo-7-chloro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylicAcid (Structure 32 of Scheme IX where X=O, R1=H, R2=H, R3=Cl, R4=H,R5=12-Br, R10=H)

This compound was prepared by general method 21 to afford crystals as amixture of cis and trans 1/1 (16.4 g, 83.6%) and, after extraction ofthe eluent, also as a mixture of cis and trans 1/1 (1.91 g, 9.7%).

trans-(12-Bromo-7-chloro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicAcid 1-methylethyl Ester (Structure 33 of Scheme IX where X=O, R1=H,R2=H, R3=Cl, R4=H, R5=12-Br, R10=H, R22=CH(CH₃)₂)

To a solution oftrans-12-bromo-7-chloro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylicacid (18.3 g, 43.3 mmol) in toluene, triethylamine (10.8 mL, 77.9 mmol)and DPPA (12.2 mL, 56.3 mmol) were added. The reaction mixture washeated to reflux for 3 h. At 100° C., 2-propanol (6.6 mL, 86.5 mmol) wasadded and stirring was continued for 3 h at 110° C. The reaction mixturewas poured into water, and extracted with ethyl acetate. The organiclayer was washed with water and brine, dried (Na₂SO₄) and evaporated,which resulted in the crude title compound (25.4 g, 100%) as a mixtureof isomers cis and trans 20:80. Data: (m/z)=479+481 (M+H)⁺.

trans-(12-Bromo-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicAcid 1-methylethyl Ester (Structure 34 of Scheme IX where X=O, R1=H,R2=H, R3=Cl, R4=H, R5=12-Br, R10=H, R22=CH(CH₃)₂)

Borane (1.0 M in THF, 216.5 mL, 216.5 mmol) was added dropwise to astirred solution oftrans-(12-bromo-7-chloro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicacid 1-methylethyl ester (25.4 g, 43.3 mmol) in THF. The resultingmixture was stirred at ambient temperature for 1 h. Water was added tothe mixture until evolution of gas ceased. More water was added and theproduct was collected by filtration. The solid was dried at 40° C. underreduced pressure for 48 h to give crystals as a mixture of trans (86%)and cis (14%). The filtrate was extracted with CH₂Cl₂. The organic layerwas washed with brine, dried (Na₂SO₄) and evaporated to give the crudeproduct (9.5 g, 47.2%) as a mixture of isomers, cis/trans=1/2. CH₂Cl₂was added to the crystals mentioned above and the pure trans isomer (5.9g, 29.3%) was collected by filtration and dried under reduced pressure.The eluent was concentrated to give a mixture of cis and trans products(7.9 g, 39.2%). Data: (m/z)=465+467 (M+H)⁺.

trans-12-Bromo-7-chloro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(Structure 35 of Scheme VIII where X=O, R1=H, R2=H, R3=Cl, R4=H,R5=12-Br, R10=H)

A mixture of acetic acid (30 mL) and hydrogen bromide (48%, 15 mL) wasadded totrans-(12-bromo-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicacid 1-methylethyl ester (5.9 g, 12.7 mmol, pure trans isomer) andstirred for 1 h at 100° C. under nitrogen. After cooling down theproduct was collected by filtration and dissolved in CH₂Cl₂. The organiclayer was washed with 2N NaOH (aq), sat. NaHCO₃ (aq), brine, dried(Na₂SO₄) and evaporated to give the title compound (4.0 g, 83%).

trans-N-(12-Bromo-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 55 of Scheme XIII)

This compound was prepared by general method 25 to afford the titlecompound (2.45 g, 90%). Data: ¹H-NMR (400 MHz, DMSO) 1.6-1.86 (m, 4H),2.1 (m, 1H), 3.12 (td, J=2.8, 13.4, 1H), 3.86 (d, J=14, 1H), 4.12 (d,J=10.4, 1H), 4.4 (m, 1H), 6.73-7.49 (6 ArH), 9.21 (d, J=10, 1NH).(m/z)=475+477 (M+H)⁺.

Example 69trans-7-Chloro-2,3,4,14b-tetrahydro-1-[(trifluoroacetyl)amino]-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-12-carbonitrile(Structure 56 of Scheme XIV)

This compound was prepared by general method 27 to afford the titlecompound (4.7 mg, 3.5%). Data: ¹H-NMR (400 MHz, DMSO) 1.60-1.88 (m, 4H),2.03 (m, 1H), 3.14 (td, J=3.2, 13.2, 1H), 3.85 (d, J=13.6, 1H), 4.21 (d,J=10, 1H), 4.4 (m, 1H), 6.77-7.70 (7 ArH), 9.26 (d, J=9.6, 1 NH).

Example 70trans-N-(7-Chloro-2,3,4,14b-tetrahydro12-methyl-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 57 of Scheme XIV)

To a solution oftrans-N-(12-bromo-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido-[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(80 mg, 0.17 mmol) in THF (2 mL) was added ferrocene PdCl₂ (5 mg, 7μmol), and the reaction mixture was stirred for 5 min. Methylzincchloride was added dropwise whereafter the reaction mixture was heatedto 60° C. and stirred overnight at 60° C. The mixture was poured intosat (aq) NH₄Cl and extracted with ethyl acetate (3×). The combinedorganic layers were washed with brine, dried (Na₂SO₄) and evaporated.After purification on silica and with HPLC the title compound wasobtained (13.2 mg, 19%). Data: ¹H-NMR (400 MHz, DMSO) 1.60-1.85 (m, 3H),2.0 (m, 1H), 2.23 (s, 3H), 3.11 (td, J=2.8, 13.2, 1H), 3.85 (d, J=14,1H), 4.10 (d, J=10, 1H), 4.40 (m, 1H), 6.69-7.10 (6 ArH), 9.16 (d, J=10,1H).

Example 71trans-N-(12-Bromo-6,7-dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 58 of Scheme XIV)

To a suspension oftrans-N-(12-bromo-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(100 mg, 0.21 mmol) in acetone was added NCS (28.7 mg, 0.21 mmol) and 6N(aq) HCl (0.4 mL, 2.4 mmol). The resulting reaction mixture was stirredovernight. A second portion of NCS (28.7 mg, 0.21 mmol) was added andstirring was continued overnight. A further amount of NCS (28.7 mg, 0.21mmol) was added and stirring was continued for 5 h. The reaction mixturewas poured into sat. (aq) NaHCO₃ and extracted with ethyl acetate (2×).The combined organic layers were washed with brine, dried (Na₂SO₄) andevaporated. After purification of the crude product with HPLC threeproducts were obtained:trans-N-(12-bromo-6,7-dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(structure 53 of scheme XIII) (13.9 mg, 13%),trans-N-(12-bromo-7,8-dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(15.7 mg, 14.1%) andtrans-N-(12-bromo-6,7,8-trichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(20.4 mg, 17.8%). Data (Structure 53): ¹H-NMR (400 MHz, DMSO) 1.55 (m,1H), 1.78 (m, 2H), 1.99 (m, 1H), 3.20 (t, J=12, 1H), 3.46 (d, J=14, 1H),4.30 (d, J=8.8, 1H), 4.45 (br.s, 1H), 7.16-7.55 (6 ArH), 9.26 (d, J=6,1NH).

Example 72trans-N-(7-Chloro-11-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 61 of Scheme XV where R5=11-F, R10=H)4-Bromo-2-[(2,3-difluorophenyl)methyleneamino]phenol (Structure 59 ofScheme XV where R5=3-F and R10=H)

2,3-Difluorobenzaldehyde (0.55 mL, 5 mmol) was added to a stirredsolution of 5-chloro-2-hydroxyaniline (0.72 g, 5 mmol) in ethanol (5mL). Within a few minutes a solid was formed and an additional amount ofethanol (10 mL) was added. The solid was isolated by filtration anddried to give the title compound (1.09 g, 81%).

8-Chloro-4-fluorodibenzo[b,f][1,4]oxazepine (Structure 60 from Scheme XVwhere R5=4-F, R10=H)

A solution of 4-bromo-2-[(2,3-difluorophenyl)methyleneamino]phenol (1.09g, 4.1 mmol) in DMSO (2.4 mL) and diethylamine (1.2 mL) was heated in amicrowave oven at 160° C. After 5 minutes the reaction mixture wasallowed to cool and water was added. Filtration and drying gave thetitle compound (0.59 g, 57%).

trans-7-Chloro-11-fluoro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylicAcid (Structure 32 of Scheme IX where X=O, R1=H, R2=H, R3=Cl, R4=H,R5=11-F, R10=H)

A solution of 8-chloro-4-fluorodibenzo[b,f][1,4]oxazepine (0.59 g, 2.4mmol) and glutaric anhydride (0.36 g, 3.2 mmol) in xylene (1.3 mL) wasstirred at 140° C. After 72 hours the reaction mixture was allowed tocool to room temperature and ether was added. Filtration gave a solidmaterial. This solid was dissolved in ethyl acetate and extracted withaqueous 2N sodium hydroxide. 3 N Hydrochloric acid was added to theaqueous extract until pH 3 and subsequently extracted with ethylacetate. The organic extract was washed with water and brine, dried(Na₂SO₄) and concentrated to give the title compound (0.44 g, 50%).

trans-(7-Chloro-11-fluoro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicAcid 1-methylethyl Ester (Structure 33 of Scheme IX where X=O, R1=H,R2=H, R3=Cl, R4=H, R5=11-F, R10=H, R22=CH(CH₃)₂)

General Method 22 was applied totrans-7-chloro-11-fluoro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylicacid (0.44 g, 1.2 mmol) and using 2-propanol instead of 3-pentanolaffordedtrans-(7-chloro-11-fluoro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicacid 1-methylethyl ester (0.63 g, 82%).

trans-(7-Chloro-11-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicAcid 1-methylethyl Ester (Structure 34 of Scheme IX where X=O, R1=H,R2=H, R3=Cl, R4=H, R5=11-F, R10=H, R22=CH(CH₃)₂)

General method 23 was applied totrans-(7-chloro-11-fluoro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicacid 1-methylethyl ester (0.63 g, 0.98 mmol) to give the crude titlecompound. Purification by column chromatography on silica gel withheptanes/ethyl acetate=4/1 yielded the title compound (0.14 g, 35%).

trans-7-Chloro-11-fluoro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(Structure 35 of Scheme VIII where X=O, R1=H, R2=H. R3=Cl, R4=H,R5=11-F, R10=H)

General method 24 was applied totrans-(7-chloro-11-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicacid 1-methylethyl ester (0.14 g, 0.35 mmol) to give the crude titlecompound. Purification by column chromatography on silica gel withheptanes/ethyl acetate yieldedtrans-7-chloro-11-fluoro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(0.14 g, 35%).

trans-N-(7-Chloro-11-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 61 of Scheme XV where R5=11-F and R10=H)

Preparation according to general method 25 usingtrans-7-chloro-11-fluoro-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(94 mg, 0.29 mmol) delivered the crude title compound. This compound waspurified by column chromatography on silica gel with heptanes/ethylacetate followed by column chromatography on silica gel withtoluene/ethyl acetate=9/1 to yield the title compound (58 mg, 48%).Data: ¹H-NMR (400 MHz, DMSO d6) 1.60-1.92 (m, 3H), 1.99-2.07 (m, 1H),3.10-3.18 (m, 1H), 3.90 (br.d, J=14, 1H), 4.19 (d, J=10 Hz, 1H),4.39-4.49 (m, 1H), 6.75 (dd, J=3, 9, 1H), 6.98-7.11 (m, 4H), 7.20-7.27(m, 1H), 9.22 (d, J=9, 1H).

Example 73trans-N-(7-Chloro-14-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 61 of Scheme XV where R5=14-F and R10=H)

Preparation according to the procedures described in Example 72 fortrans-N-(7-chloro-11-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamidestarting from 2,6-difluorobenzaldehyde (0.54 mL, 5 mmol) delivered thecrude title compound. This compound was purified by columnchromatography on silica gel with heptanes/ethyl acetate, columnchromatography on silica gel with toluene/ethyl acetate=9/1 and finallycrystallization from acetonitrile to yield the title compound (136 mg,6% overall yield). Data: ¹H-NMR (400 MHz, DMSO d6) 1.57-1.76 (m, 2H),1.89-2.04 (m, 2H), 3.09-3.18 (m, 1H), 3.93 (br.d, J=14, 1H), 4.42 (d,J=10, 1H), 4.52-4.62 (m, 1H), 6.74 (dd, J=9, 3, 1H), 6.95-7.16 (m, 4H),7.27-7.33 (m, 1H), 9.30 (d, J=9, 1H).

Example 74trans-N-(7-Chloro-12-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 61 of Scheme XV where R5=12-F and R10=H)

Preparation according to the procedures described in Example 72 fortrans-N-(7-chloro-11-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamidestarting from 2,4-difluorobenzaldehyde (0.55 mL, 5 mmol) delivered thecrude title compound. This compound was purified by columnchromatography on silica gel with heptanes/ethyl acetate and HPLC on aLuna column (10u C(18(2), 250×50 mm) using a gradient ofacetonitrile/water to acetonitrile in 30 minutes at a flow of 50 mL/min.to yield the title compound (62 mg, 3% overall yield). Data: ¹H-NMR (400MHz, DMSO d6) 1.59-1.86 (m, 3H), 1.98-2.06 (m, 1H), 3.08-3.17 (m, 1H),3.87 (br.d, J=13, 1H), 4.13 (d, J=10, 1H), 4.35-4.45 (m, 1H), 6.76 (dd,J=8, 3, 1H), 6.92-6.98 (m, 1H), 7.08 (s, 1H), 7.12-7.23 (m, 3H), 9.18(d, J=9, 1H).

Example 75trans-N-(7-Chloro-12,13-difluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 61 of Scheme XV where R1=H, R2=H, R3=Cl, R4=H, R5=12-F,R10=13-F) 4-Bromo-2-[(2,4,5-trifluorophenyl)methyleneamino]phenol(Structure 59 of Scheme XV where where R5=4-F, R10=5-F)

2,4,5-Trifluorobenzaldehyde (0.56 mL, 5 mmol) was added to a stirredsolution of 5-chloro-2-hydroxyaniline (0.72 g, 5 mmol) in ethanol (5mL). Within minutes a solid was formed and an additional amount ofethanol (10 mL) was added. The solid was isolated by filtration anddried to give the desired product (1.17 g, 82%).

8-Chloro-2,3-difluorodibenzo[b,f][1,4]oxazepine (Structure 60 of SchemeXV where where R5=3-F, R10=2-F)

A solution of 4-bromo-2-[(2,4,5-trifluorophenyl)methyleneamino]Phenol(1.17 g, 4.1 mmol) in DMSO (2.4 mL) and N,N-diisopropylethylamine (1.2mL) was heated in a microwave oven at 160° C. After 5 minutes thereaction mixture was allowed to cool and water was added. Filtration anddrying gave the title compound (1.03 g, 95%).

trans-N-(7-Chloro-12,13-difluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 61 of Scheme XV where R5=12-F and R10=13-F)

The procedure described in Example 72 for the preparation oftrans-N-(7-chloro-11-fluoro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 61 of scheme XV where R5=11-F, R10=H) from intermediate8-chloro-4-fluorodibenzo[b,f][1,4]oxazepine (Structure 60 of scheme XV)was applied to 8-chloro-2,3-difluorodibenzo[b,f][1.4]oxazepine(Structure 60 of scheme XV where R5=3-F and R10=2-F) (1.03 g, 3.87mmol). The crude product was purified by column chromatography on silicagel with toluene/ethyl acetate=9/1 to give the title compound (44 mg, 3%overall yield). Data: ¹H-NMR (400 MHz, CDCl₃): 1.66(dq, J=12, 4.5, 1H),1.80-1.92(m, 2H), 2.28-2.34(m, 1H), 3.19(m, 1H), 3.86(m, 1H), 4.30(d,J=10, 1H), 4.66(m, 1H), 6.02(m, 1H), 6.59(m, 1H), 6.72(dd, J=8.8 3.2,1H), 6.79(m, 1H), 6.90(d, J=3.2, 1H), 7.02(d, J=8, 1H).

Example 76trans-N-(7-Chloro-1,2,3,4,10,14b-hexahydro-10-methyl-dibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 67 of scheme XVI)4-Chloro-N-methyl-2-nitro-N-phenylphenylamine (Structure 62 of SchemeXVI)

4-Chloro-1-fluoro-2-nitrobenzene (20.0 g, 0.11 mol) and K₂CO₃ (15.7 g,0.11 mol) were dissolved in N-methylaniline (37 mL, 0.34 mol) andsubsequently heated to 180° C. After 5 h, the reaction mixture wascooled to room temperature, diluted with CH₂Cl₂ (750 mL) and washed withH₂O (500 mL), aq. citric acid (5% 500 mL) and brine (500 mL). Theorganic layer was dried (Na₂SO₄) and concentrated under reducedpressure. The residual oil was chromatographed over silica(cyclohexane/CH₂Cl₂, 9/1, v/v) giving title compound containing 30%starting material. The compound was subsequently stirred in cold hexaneand the resulting red crystals were filtered resulting in purecrystalline product (16.5 g, 57% yield). Data: melting point: 59-62° C.,Rf 0.65 (cyclohexane/ethyl acetate, 4/1, v/v).

4-Chloro-N′-methyl-N′-phenylbenzene-1,2-diamine (Structure 63 of SchemeXVI)

To a solution of 4-chloro-N-methyl-2-nitro-N-phenylphenylamine (12.5 g,46.3 mmol) in ethanol (250 mL) was added SnCl₂.2H₂O (37.5 gr., 0.17mol). The solution was heated to 40° C. and stirred for 6 h. Thereaction mixture was concentrated in vacuo and subsequently diluted withethyl acetate (500 mL) and washed with H 20 (500 mL), a cooled (0° C.)aq. solution of NaOH (1 M, 200 mL), H₂O (500 mL) and brine (500 mL). Theorganic layer was dried (Na₂SO₄), filtered and concentrated underreduced presssure. The crude compound was applied onto a silica columnand eluted with heptane/ethyl acetate (8/2, v/v) affording the titlecompound (9.3 g, 87% yield). Data: Rf 0.65 (heptane/ethyl acetate, 7/3,v/v), (m/z)=233 (M+H)⁺.

N-[5-chloro-2-(methylphenylamino)phenyl]formamide (Structure 64 ofScheme XVI)

4-Chloro-N¹-methyl-N¹-phenylbenzene-1,2-diamine (9.3 g, 40.1 mmol) wasdissolved in formic acid (60 mL) and heated to reflux. After 2 h, thereaction mixture was concentrated in vacuo. The residue was dissolved inethyl acetate (500 mL) and washed with aq. NaHCO₃ (5%, 500 mL). Theorganic layer was dried, filtered and concentrated under reducedpressure. The residual oil was chromatographed over silica(cyclohexane/CH₂Cl₂, 9/1, v/v) to give pure title compound (10.4 g, 100%yield). Data: Rf 0.25 (heptane/ethyl acetate, 3/1, v/v). (m/z)=261(M+H)⁺.

3-chloro-5-methyl-5H-dibenzo[b,f][1,4]diazepine (Structure 65 of SchemeXVI)

To a three-necked flask was added PPA (150 g), which was subsequentlyheated to 120° C. and vigorously stirred. POCl₃ was added dropwise over90 minutes (caution: foaming) after which formamide (10.4 g, 40.1 mmol)was added to the reaction mixture in 4 consecutive portions. Thereaction mixture was stirred for 2 h at 120° C. and then cooled to roomtemperature. aq. NaHCO₃ (300 mL) was cautiously added to the reactionmixture and the reaction mixture was neutralized by further additions ofNaHCO₃ (s) until pH 8. Subsequently, ethyl acetate (1 L) was added andthe salts were removed by filtration. The organic layer was washed withH 20 (500 mL) and brine (500 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification by silica gel column chromatography(heptane/ethyl acetate, 8/2, v/v) afforded pure3-chloro-5-methyl-5H-dibenzo[b,f][1,4]diazepine (8.8 g, 91% yield).(m/z)=243 (M+H)⁺.

trans-7-Chloro-1,2,3,4,10,14b-hexahydro-10-methyl-4-oxodibenzo[b,f]pyrido[1,2-d][1,4]diazepine-1-carboxylicAcid (Structure 32 of Scheme IX, where X=N (Me), R1=H, R2=H, R3=Cl,R4=H, R5=H, R10=H)

A solution of 3-chloro-5-methyl-5H-dibenzo[b,f][1,4]diazepine (1.0 g,4.1 mmol) and glutaric anhydride (0.64 g, 5.6 mmol) in xylene (2.5 mL)was stirred at 140° C. After 48 hours the reaction mixture was allowedto cool to room temperature and ether was added. Filtration gave thetitle compound (1.1 g, 72%) as a solid.

trans-(7-Chloro-1,2,3,4,10,14b-hexahydro-10-methyl-4-oxodibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)carbamicAcid Methyl Ester (Structure 33 of Scheme IX, where X=N(Me), R1=H, R2=H,R3=Cl, R4=H, R5=H, R10=H, R22=CH₃)

General method 22 was applied totrans-7-chloro-1,2,3,4,10,14b-hexahydro-10-methyl-4-oxodibenzo[b,f]pyrido[1,2-d][1,4]diazepine-1-carboxylicacid (1.1 g, 3.0 mmol) and using methanol as alcohol afforded crudetitle compound (1.4 g, 100%) that was used in the next synthetic stepwithout further purification.

trans-7-Chloro-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)carbamicAcid Methyl Ester (Structure 34 of Scheme IX, where X=N(Me), R1=H, R2=H,R3=Cl, R4=H, R5=H, R10=H, R22=CH₃)

General method 23 was applied totrans-7-chloro-1,2,3,4,10,14b-hexahydro-10-methyl-4-oxodibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)carbamicAcid Methyl Ester (1.4 g, 100%) to give the crude title compound. Thisresidue was triturated with ether to give the title compound (0.67 g,61%) as a solid.

trans-7-Chloro-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[b,f]pyrido[1,2-d][1,4]diazepine-1-amine(Structure 35 of Scheme IX, where X=N(Me), R1=H, R2=H, R3=Cl, R4=H,R5=H, R10=H)

General method 24 was applied totrans-7-chloro-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)carbamicacid methyl ester (0.67 g, 1.8 mmol) to give the crude title compound asa solution in ethyl acetate (100 mL). A solid material was formed uponstorage at 5° C. for 16 hours. This solid was isolated (0.15 g, 21%) andthe mother liquor was concentrated. The residue was treated with ether.The resulting solids were removed by filtration and the filtrateconcentrated to give additional title compound (0.32 g, 56%). Bothquantities of title compound were used in the next step without furtherpurification.

trans-N-(7-Chloro-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[b,f]pyrido[1,2-d][1,4]-diazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 67 of Scheme XVI)

Preparation according to general method 25 usingtrans-7-chloro-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[b,f]pyrido[1,2-d][1,4]diazepine-1-amine(0.25 g, 0.69 mmol) delivered the crude title compound. This residue wastriturated with ether to give the title compound (0.17 g, 60%) as asolid. Data: ¹H-NMR (400 MHz, CDCl₃) 1.62-1.89 (m, 3H), 2.27 (dq, J=5.0,5.0, 12.4, 1H), 3.20 (m, 1H), 3.30 (s, 3H), 3.63 (m, 1H), 4.08 (m, 1H),4.80 (m, 1H), 6.07 (br, 1NH), 6.71-7.27 (m, 7 ArH).

Example 77trans-[(7-Chloro-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)amino]aceticAcid (Structure 69 of Scheme XVI) Ethyltrans-[(7-chloro-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)amino]acetate(Structure 68 of Scheme XVI)

To a suspension oftrans-7-chloro-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[b,f]pyrido[1,2-d][1,4]-diazepin-1-ylamine(100 mg, 0.25 mmol) in DMF (2 mL) was added ethyl bromoacetate (56 μl,0.51 mmol) and triethylamine (107 ul, 0.76 mmol). The resulting reactionmixture was heated to 60° C. and stirred for 5 h. The mixture was pouredinto water and extracted with ethyl acetate (3×). The organic layerswere washed with sat (aq) NaHCO₃ and brine. After drying (MgSO₄), thesolvents were removed under reduced pressure. The crude product waspurified on silica with heptane/ethyl acetate 8:2 to afford 80 mg (80%)of the title compound.

trans-[(7-Chloro-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)amino]aceticAcid (Structure 69 of Scheme XVI)

To a solution of ethyltrans-[(7-chloro-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)amino]acetate(35 mg, 0.09 mmol) in dioxane (1 mL) was added 4N (aq) NaOH (250 ul).The reaction mixture was stirred at 65° C. for 1.5 h. It was dilutedwith water (25 mL) whereafter the pH was adjusted to pH 2 with 2N (aq)HCL. The mixture was extracted with ethyl acetate (2×), washed withwater and brine, dried (MgSO₄) and evaporated. The crude product waspurified with LC-MS to afford the title compound (4 mg, 12%). Data(m/z)=372 (M+H)⁺.

Example 78trans-N-(7-chloro-1,2,3,4,10,14b-hexahydrodibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 75 of Scheme XVII) 2-[(4-Chloro-2-nitrophenyl)amino]benzoicAcid (Structure 70 of Scheme XVII)

A solution of 4-chloro-1-fluoro-2-nitrobenzene (20 g, 114 mmol) andanthranilic acid (17.4 g, 127 mmol) in pentanol (250 mL) was heated to120° C. in a Dean-Stark apparatus. Copper (126 mg, 2 mmol) was added,followed by potassium carbonate (12.7 g, 92 mmol). The resultingreaction mixture was stirred at 120° C. for 0.5 h and at 140° C. for 2h. Subsequently, water and 1N (aq.) NaOH were added to dissolve theproduct. Then, the pH was adjusted to pH 5 and the water layer wasextracted with ethyl acetate (3×). The combined organic layers werewashed with water and brine, dried and evaporated. Ethanol was added tothe obtained product. The title compound (14.4 g, 43%) was collected byfiltration of the ethanol mixture.

2-[(2-Amino-4-chlorophenyl)amino]benzoic Acid (Structure 71 of SchemeXVI)

To a solution of 2-[(4-chloro-2-nitrophenyl)amino]benzoic acid (12.8 g,43.7 mmol) in ethyl acetate (300 mL) was added platinum on sulfide coal5%. The reaction mixture was hydrogenated at 2 bar for 5 h. Afterfiltration through dicalite, washing with ethyl acetate and removal ofthe solvent under reduced pressure the title compound (11.8 g, 100%) wasobtained.

8-Chloro-5,10-dihydrodibenzo[b,f][1,4]diazepin-11-one (Structure 72 ofScheme XVII)

A solution of 2-[(2-amino-4-chlorophenyl)amino]benzoic acid (11.8 g, 45mmol) in xylene (150 mL) was heated to reflux in a Dean-Stark apparatus.The reaction mixture was stirred at reflux temperature for 31 h. Afterremoval of the xylene in vacuo, the title compound was obtained. Therewas still starting material present. Therefore the product was dissolvedin xylene (150 mL) again and stirring was continued overnight at refluxtemperature in a Dean-Stark apparatus. After removal of the xylene underreduced pressure the title compound (12.4 g, 50.6 mmol) was obtained.

8-Chloro-10,11-dihydro-5H-dibenzo[b,f][1,4]diazepine (Structure 73 ofScheme XVII)

THF (250 mL) was cooled to 0° C. whereafter LiAlH₄ (6.7 g, 177 mmol) wasadded portionwise. Subsequently,8-chloro-5,10-dihydrodibenzo[b,f][1,4]diazepin-11-one (12.4 g, 45 mmol)was added portionwise followed by THF (100 mL). The resulting reactionmixture was heated to reflux and stirred overnight at refluxtemperature. After cooling down the mixture to 0° C., sat. (aq) Na₂SO₄was added dropwise. Stirring was continued for 15 minutes, whereafterthe reaction mixture was filtrated through dicalite. The volatiles wereremoved under reduced pressure to afford the crude product. A mixture oftoluene and ethyl acetate was added to the crude product. The solidmaterial (5.4 g, 52%) was collected through flitration, followed bydrying overnight at 40° C. under reduced pressure.

8-Chloro-5H-dibenzo[b,f][1,4]diazepine (Structure 74 of Scheme XVII)

To a solution of 8-chloro-10,11-dihydro-5H-dibenzo[b,f][1,4]diazepine(8.75 g, 37.9 mmol) in CH₂Cl₂ (375 mL) was added MnO₂ (14.5 g, 166mmol). The reaction mixture was stirred at room temperature for 1.5 h.After filtration through dicalite, washing with CH₂Cl₂, the volatileswere removed in vacuo. The crude product was dissolved in ethanol (250mL) wherafter 2N (aq) NaOH (20 mL) was added. This mixture was stirredat room temperature for 2.5 h. The reaction mixture was filtratedthrough dicalite and washed with CH₂Cl₂. After removal of the solventunder reduced pressure, the residu was dissolved in ethanol (350 mL).NaOH (2N, 20 mL) was added and the mixture was stirred for 3 h. Waterwas added and the mixture was extracted with ethyl acetate (3×). Thecombined organic layers were washed with brine, dried and evaporated toafford the title compound (8.9 g, 38.9 mmol).

trans-7-Chloro-1,2,3,4,10,14b-hexahydro-4-oxodibenzo[b,f]pyrido[1,2-d][1,4]diazepine-1-carboxylicAcid (Structure 32 of Scheme IX where X=N(H), R1=H, R2=H, R3=Cl, R4=H,R5=H, R10=H)

This compound was prepared by general method 21, after acid/baseextraction of the reaction mixture to afford the crude title compound(4.4 g, 34%).

trans-7-Chloro-1,2,3,4,10,14b-hexahydro-4-oxodibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)carbamicAcid Methyl Ester (Structure 33 of Scheme IX where X=N(H), R1=H, R2=H,R3=Cl, R4=H, R5=H, R10=H, R22=CH₃)

This compound was prepared by general method 22. Methanol was used asalcohol to afford the crude title compound (437 mg, >100%).

trans-7-Chloro-1,2,3,4,10,14b-hexahydrodibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)carbamicAcid Methyl Ester (Structure 34 of Scheme IX where X=N(H), R1=H, R2=H,R3=Cl, R4=H, R5=H, R10=H, R22=CH₃)

This compound was prepared by general method 23 to afford the crudetitle compound (0.51 g, 100%).

trans-7-Chloro-1,2,3,4,10,14b-hexahydrodibenzo[b,f]pyrido[1,2-d][1,4]diazepine-1-amine(Structure 35 of Scheme IX where X=N(H), R1=H, R2=H, R3=Cl, R4=H, R5=H,R10=H)

To a solution oftrans-7-chloro-1,2,3,4,10,14b-hexahydrodibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)carbamicacid methyl ester (0.51 g, 0.95 mmol) in ethylene glycol (6 mL) wasadded KOH (0.37 g, 6.6 mmol). The reaction mixture was heated to 100° C.and stirred overnight at 140° C. After cooling of the reaction mixturewater and ethyl acetate were added. The mixture was extracted with ethylacetate (3×). The organic layers were washed with water and brine, dried(Na₂SO₄) and evaporated to give the crude product (350 mg, 100%).

trans-N-(7-Chloro-1,2,3,4,10,14b-hexahydrodibenzo[b,f]pyrido[1,2-d][1,4]diazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 75 of Scheme XVII)

To a solution oftrans-7-chloro-1,2,3,4,10,14b-hexahydrodibenzo[b,f]pyrido[1,2-d][1,4]diazepine-1-amine(Structure 35 of scheme IX where X=N(H), R1=H, R2=H, R3=Cl, R4=H, R5=H,R10=H) (350 mg, 1,17 mmol) in methanol (22 mL) and triethylamine (0.7mL) was added ethyl trifluoroacetate (1.5 mL). The reaction mixture wasstirred at room temperature for 3 h. Water was added and the mixture wasextracted with ethyl acetate (3×). The organic layers were washed withbrine, dried (Na₂SO₄) and evaporated. After purification on silica withheptane/ethyl acetate 6:4 the title compound (90 mg, 19%) was obtained.Data: ¹H-NMR (400 MHz, CDCl₃) 1.69 (m, 1H), 1.86-1.94 (m, 2H), 2.11 (m,1H), 2.99-3.09 (m, 2H), 4.47 (d, 1H), 4.86 (m, 1H), 5.79 (s, 1H, NH),6.62 (d, J=8.2, 1H), 6.75 (dd, J=7.8, 1H), 6.89 (t, J=7.8, 1H), 6.91(dd, J=8.2, J=2.7, 1H), 7.10 (d, J=2.7, 1H), 7.18 (t, J=7.8, 1H), 7.24(d, J=7.8, 1H).

Examples 79A and B(1α,2β,14bα)-N-(7-Chloro-2,3,4,14b-tetrahydro-2-methyl-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 86 of Scheme XVIII)(1α,2α,14bα)-N-(7-Chloro-2,3,4,14b-tetrahydro-2-methyl-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 87 of Scheme XVIII) N-(5-Chloro-2-phenoxyphenyl)formamide(Structure 76 of Scheme XVIII)

This compound was generated by general method 29 from5-chloro-2-phenoxybenzeneamine to affordN-(5-chloro-2-phenoxyphenyl)formamide (29.5 g, 94%). (m/z)=248 (M+H)⁺.

8-Chlorodibenzo[b,f][1,4]oxazepine (Structure 77 of Scheme XVIII)

This compound was generated by general method 30 to afford8-Chlorodibenzo[b,f][1,4]oxazepine (24.5 g, 89%). (m/z)=230 (M+H)⁺.

trans-7-Chloro-2-methyl-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-carboxylicAcid (Structure 78 of Scheme XVIII)

This compound was generated by general method 21 by using3-methylglutaric anhydride (4). A mixture of two isomers (1/1) (2.2 g,66%) was obtained by crystallisation from diethyl ether. (m/z)=358(M+H)⁺.

trans-(7-Chloro-2-methyl-2,3,4,14b-tetrahydro-4-oxo-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicAcid Methyl Ester (Structure 79 of Scheme XVIII)

This compound was generated by general method 22 by using methanol asalcohol to afford the crude title compound (2.6 g, >100%). (m/z)=387(M+H)⁺.

trans-(7-Chloro-2-methyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicAcid Methyl Ester (Structures 80, 81 and 82 of Scheme XVIII)

This compound was generated by general method 23. The crude product waschromatographed with heptane/ethyl acetate 6:4 to afford(1α,2β,14bα)-(7-chloro-2-methyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicacid methyl ester (Structure 82 of scheme XVII) (301 mg, 11%, trans) anda mixture of two other isomers(1α,2α,14bα)-(7-chloro-2-methyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicacid methyl ester (Structure 80 of scheme XVIII) and(1α,2α,14bβ)-(7-chloro-2-methyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicacid methyl ester (Structure 81 of scheme XVIII) (1.6 g, 63%, trans andcis). (m/z)=373 (M+H)⁺.

trans-7-Chloro-2-methyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(Structures 83 and 84 of Scheme XVIII

This compound was generated by general method 24 starting with a mixtureof(1α,2α,14bα)-(7-chloro-2-methyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicacid methyl ester (Structure 80 of scheme XVII) and(1α,2α,14bβ)-(7-chloro-2-methyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicacid methyl ester (Structure 81 of scheme XVII) to afford a mixture oftwo isomers(1α,2α,14bα)-7-chloro-2-methyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(Structure 83 of scheme XVII) and(1α,2α,14bβ)-7-chloro-2-methyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(Structure 84 of scheme XVII) (1.3 g, 96%).

(1α,2β,14bα)-7-chloro-2-methyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine(Structure 85 of Scheme XVII)

This compound was generated from(1α,2β,14bα)-(7-chloro-2-methyl-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)carbamicacid methyl ester by general method 24 to afford the title compound(Structure 85 from scheme XVII) (130 mg, 51%, trans).

(1α,2β,14bα)-N-(7-Chloro-2,3,4,14b-tetrahydro-2-methyl-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 86 from Scheme XVII)

This compound was generated by general method 25 starting from compound85 to afford the title compound. After purification with HPLC (53 mg,31%, trans) was obtained. Data: ¹H-NMR (400 MHz, CDCl₃) 1.02-1.04 (d,J=6.4, 3H), 1.58 (m, 1H), 1.78 (m, 1H), 1.98 (m, 1H), 3.22-3.31 (td,J=12.2, J=2.2, 1H), 3.91 (m, 1H), 4.13-4.18 (d, J=10.0, 1H), 4.23-4.30(t, J=10.0, 1H), 6.64-7.27 (7 ArH). (m/z)=411 (M+H)⁺.

(1α,2α,14bα)-N-(7-Chloro-2,3,4,14b-tetrahydro-2-methyl-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide(Structure 87 from Scheme XVII)

This compound was generated by general method 25 starting with a mixtureof isomers 83 and 84 to afford a mixture of products 87 and 88. Afterpurification with HPLC the title compound (115 mg, 13%) was obtained.Data: ¹H-NMR (400 MHz, DMSO) 1.00-1.04 (d, J=7.0, 3H), 1.73-1.79 (q,J=6.0, 2H), 2.24-2.35 (m, 1H), 3.31-3.52 (m, 2H), 4.55-4.60 (d, J=8.3,1H), 4.65-4.72 (m, 1H), 6.71-7.38 (7 ArH), 9.07-9.12 (d, J=9.8, NH).(m/z)=411 (M+H)⁺.

Example 80

Progesterone Receptor-B Activity in a Transactivation.

The (anti-)progestagenic activity of a compound of the invention (EC 50and intrinsic activity) was determined in an in vitro bioassay ofChinese hamster ovary (CHO) cells stably transfected with the humanprogesterone receptor-B expression plasmid and with a reporter plasmidin which the MMTV-promoter is linked to the luciferase reporter gene.The cell-line is known under the name CHO-PRB-pMMTV-LUC 1E2-A2 (DijkemaR et al (1998) J Steroid Biochem Mol Biol, 64: 147-56). The cells werecultured with charcoal-treated supplemented defined bovine calf serumfrom Hyclone (Utah, USA) in Dulbecco's Modified Eagles Medium/NutrientMixture F-12 (DMEM/HAM F12 in ratio 1:1) from Gibco (Paisley, UK).

The antiprogestagenic activity of a compound of the invention wasdetermined by the inhibition of the transactivation via the progesteronereceptor-B of the enzyme luciferase in the presence of 1 nM(16α)-16-ethyl-21-hydroxy-19-norpregn-4-ene-3,20-dione and compared withthe reference antiprogestagen(6β,11β,17β)-11-[4-(dimethylamino)phenyl]-4′,5′-dihydro-6-methylspiro[estra-4,9-diene-17,2′(3′H)-furan]-3-one,the activity of which was set at 100%. Agonistic ligands do not inhibittransactivation of luciferase activity induced by 0.1 nM Org 2058,whereas strong and weak antiprogestagens can inhibit transactivationdependent on the dose level used.

Progestagenic activity with an EC₅₀ between 10000 and 100 nM was foundfor the compounds of Examples 1, 3, 5, 9, 10, 12, 14, 15, 16, 17, 18,27, 28, 30, 31, 36, 37, 39, 40, 42B, 43, 44, 48, 49, 50, 56, 64 and 67.The compounds of Examples 11, 13, 21, 24, 29, 38A, 45, 46, 55, 62, 68,69, 70, 72, 74, 78 and 79B showed an EC₅₀ between 100 and 10 nm, whereasthe compounds of Examples 6, 7, 8, 13 (1S14bR isomer), 19, 20, 22, 23,25, 26, 38B, 41, 42A, 47, 51, 52, 53, 54, 57, 58, 59, 60, 61, 63, 71,73, 75, 76 and 79A showed an EC₅₀<10 nM. The intrinsic activity relativeto (16α)-16-ethyl-21-hydroxy-19-norpregn-4-ene-3,20-dione was >10% inall compounds tested.

Anti-progestagenic activity with an EC₅₀ between 10000 and 100 nM wasfound for the compounds of Examples 5, 9, 10, 15, 21, 32, 33, 35, 38A,39 and 41. The compounds of Examples 7, 8, 11, 22 (1S,14bR isomer), 29,48 and 49 showed an EC₅₀ between 100 and 10 nm, whereas the compound ofExample 13 (1S,14bR isomer) showed an EC₅₀<10 nM. The intrinsic activityrelative to(6β,11β,17β)-11-[4-(dimethylamino)phenyl]-4′,5′-dihydro-6-methylspiro[estra-4,9-diene-17,2′(3′H)-furan]-3-onewas >15% in all compounds tested.

1. A compound according to Formula I, a prodrug thereof, apharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable salt of a prodrug thereof

wherein R1, R3, R4, R5 and R10 independently are selected from the groupconsisting of H, halogen, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, OH,CN, O(1-4C)alkyl, S(O)_(m)(1-4C)alkyl, optionally substituted with oneor more halogen atoms, C(O)(1-4C)alkyl, OC(O)(1-4C)alkyl and NR19R20, R2is selected from the group consisting of H, halogen, NO₂, NR11R12,(1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, OH, O(1-4C)alkyl,S(1-4C)alkyl and OC(O)(1-4C)alkyl, R6 is selected from the groupconsisting of H, C(Y)R15, C(O)OR16, C(S)NR17, (1-6C)alkyl,(1-6C)alkoxy-substituted (1-4C)alkyl and (CH₂)_(n)C(O)OR21, R7 is H orR7 is selected from the group consisting of (1-4C)alkyl, (2-4C)alkenyland (2-4C)alkynyl, all optionally substituted with one or more halogenatoms, R8 and R9 independently are selected from the group consisting ofH and (1-4C)alkyl, R11 and R12 independently are selected from the groupconsisting of H, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl,(1-6C)alkoxycarbonyl, (1-4C)alkylsulfonyl, and (6-10C)arylsulfonyl, R15is H or R15 is selected from the group consisting of (1-6C)alkyl,(3-6C)cycloalkyl, (2-4C)alkenyl or (2-4C)alkynyl, (6-10C)aryl,1,4-bisaryl, amino(1-4C)alkyl, hydroxy(1-4C)alkyl, andcarboxy(1-4C)alkyl, all optionally substituted with one or more halogenatoms, R16 is (1-6C)alkyl, optionally substituted with one or morehalogen atoms, R17 is selected from the group consisting of (1-4C)alkyl,(2-4C)alkenyl, (2-4C)alkynyl and (3-6C)cycloalkyl, all optionallysubstituted with one or more halogen atoms, X is selected from the groupconsisting of O, S, CH₂ and NR18, Y is selected from the groupconsisting of O, S, and NH, R18 is selected from the group consisting ofH and (1-4C)alkyl, R19 is selected from the group consisting of H and(1-4C)alkyl, R20 is selected from the group consisting of H,(1-4C)alkyl, CH₂(6-10C)aryl, C(O)(1-6C)alkyl and C(O)NH(1-4C)alkyl, R21is selected from the group consisting of H and (1-6C)alkyl, m is 0, 1 or2, and n is 1, 2 or 3, provided that (i) when X is O, R1-R5 are H,R8-R10 are H. and R6 is ethyl or C(O)CH₃ then R7 is not H; (ii) when Xis O, R1-R5 are H, R8-R10 are H, and R6 is methyl then R7 is not methyl;and (iii) when X is O, R1-R5 are H. R8-R10 are H and R6 is H then R7 isnot H or ethyl or (CO)CH₃.
 2. The compound according to claim 1, whereinR2 is selected from the group consisting of H, halogen, NO₂, andNR11R12; and R11 and R12 independently are selected from the groupconsisting of H, (1-6C)alkoxycarbonyl, (1-4C)alkylsulfonyl and(6-10C)arylsulfonyl.
 3. The compound according to claim 1, wherein R1and R5 are H and R3 and R4 are selected from H or halogen.
 4. Thecompound according to claim 1, wherein X is selected from the groupconsisting of O, S and CH₂.
 5. The compound according to claim 1,wherein R6 is selected from H or C(Y)R15 and R15 is (1-4C)alkyloptionally substituted with one or more halogen atoms or H.
 6. Thecompound according to claim 1, wherein X is O or CH₂, R2 is selectedfrom the group consisting of H, halogen and NO₂ and R15 is (1-2C)alkyloptionally substituted with one or more halogen atoms.
 7. The compoundsaccording to claims 16 claim 1, wherein R11 is H and R12 is selectedfrom the group consisting of (1-6C)alkoxycarbonyl, (1-4C)alkylsulfonyland (6-10C)arylsulfonyl.
 8. The compound according to claims 1-7 claim1, wherein R2 is H, R3 is halogen, R15 is methyl, optionally substitutedwith 1-3 halogen atoms and Y is O or S.
 9. The compound according toclaim 1, wherein R4 is H and X is O.
 10. The compound according to claim1, wherein R2 is H or halogen, R3 and/or R4 are independently selectedfrom the group consisting of H, ON, halogen, (2-4C)alkenyl andC(O)(1-4C)alkyl, and R5 and/or R10 are independently selected from H orhalogen.
 11. The compound according to claim 1, wherein X is selectedfrom the group consisting of O, S and NCH₃.
 12. The compound accordingto claim 1, wherein R8 and R9 are H.
 13. The compound according to claim1, wherein R6 is H or C(Y)R15 and R15 is (1-4C)alkyl, optionallysubstituted with one or more halogen atoms, or H.
 14. The compoundaccording to claim 1, wherein Y is O or S, and R15 is methyl, optionallysubstituted with one or more halogen atoms.
 15. (canceled)
 16. Apharmaceutical composition, comprising: the compound according to claim1 and pharmaceutically acceptable auxiliaries.